The Antiplatelet Effects of Ticlopidine and Clopidogrel

  1. Peter J. Sharis, MD;
  2. Christopher P. Cannon, MD; and
  3. Joseph Loscalzo, MD, PhD
  1. From Brigham and Women's Hospital, Harvard Medical School, and Boston University School of Medicine, Boston, Massachusetts. For current author addresses, see end of text. Requests for Reprints: Joseph Loscalzo, MD, PhD, Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, 88 East Newton Street, Boston, MA 02118-2394; e-mail, jloscalz@bu.edu. Current Author Addresses: Drs. Sharis and Cannon: Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
     
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    Abstract

    Ticlopidine and clopidogrel achieve antiplatelet effects by inhibiting the binding of adenosine 5′-disphosphate to its platelet receptor. Ticlopidine was first shown to decrease major events compared with placebo or aspirin in patients with stroke or recent transient ischemic attack. Randomized studies in patients undergoing coronary artery stenting have shown that ticlopidine reduces the risk for subacute stent thrombosis compared with warfarin-based regimens. Smaller studies have also shown this drug to have benefit during follow-up in patients with unstable angina, peripheral arterial disease, saphenous vein coronary bypass grafts, and diabetic retinopathy. Clopidogrel was recently approved by the U.S. Food and Drug Administration for the reduction of ischemic events in patients with recent myocardial infarction, stroke, or peripheral arterial disease (incidence, 5.32% per year compared with 5.83% per year for aspirin; P = 0.043) with no added risk for neutropenia. The combination of clopidogrel and aspirin, as well as the utility of clopidogrel in other patient populations and in stenting, requires further study. Ticlopidine and clopidogrel seem to have beneficial effects compared with aspirin (the current standard) in a broad range of patients. These observations highlight the importance of antiplatelet therapy in cardiovascular disease.

    Antiplatelet agents are used primarily to treat and prevent arterial thrombosis. Aspirin, a relatively weak antiplatelet agent, has been shown through years of extensive experience and numerous trials to be of substantial benefit in the treatment and prevention of acute coronary syndromes [1, 2]. The newer glycoprotein IIb/IIIa inhibitors are much more potent inhibitors of platelet function and have shown great promise in clinical studies to date [3, 4], but the efficacy and side-effect profile associated with long-term administration of these agents are unclear.

    This review focuses on the mechanism of action, pharmacology, and major clinical applications of another class of antiplatelet agents-thienopyridines-that achieve moderate levels of platelet inhibition. Ticlopidine has been available for many years; it initially received approval for the secondary prevention of stroke and has also been shown to be beneficial in other clinical applications. However, its use has been limited by the significant risk for neutropenia (approximately 1%). Clopidogrel, recently approved by the U.S. Food and Drug Administration (FDA), seems to carry a minimal risk for neutropenia and will probably be more widely used.

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    Methods

    Articles published from 1966 through 1998 were identified through a MEDLINE search done by using Ovid software (Ovid Technologies, Inc., New York, New York). The reference lists of selected articles were then reviewed for additional relevant articles. Pertinent abstracts from the American Heart Association and American College of Cardiology Scientific Sessions in 1996, 1997, and 1998 were identified from a review of two major cardiology journals. Descriptive and analytical data were extracted from studies that contained information about the mechanisms of action, pharmacology, clinical uses, and side effects of ticlopidine and clopidogrel.

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    Mechanism of Action and Pharmacology

    Ticlopidine and its more recently developed analogue, clopidogrel, are thienopyridine derivatives that inhibit platelet aggregation. Clopidogrel differs structurally from ticlopidine by the addition of a carboxymethyl side group (Figure 1). Ticlopidine and clopidogrel can both be administered orally; maximal bioavailability occurs when they are taken after meals. Both agents are inactive in vitro, requiring breakdown to an unidentified active metabolite or metabolites to achieve in vivo activity [5, 6]. Activation seems to occur in the liver, and the active metabolites are primarily excreted renally [7-9].

    Figure 1.
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    Figure 1. Chemical structures of ticlopidine (top) and clopidogrel (bottom).

    Ticlopidine and clopidogrel are believed to inhibit the binding of adenosine 5′-diphosphate (ADP) to its platelet receptor (Figure 2) [10-16]. In initial studies, this ADP receptor blockade led to direct inhibition of the binding of fibrinogen to the glycoprotein IIb/IIIa complex [17-19]. Evidence also indicates that ticlopidine may interfere with von Willebrand factor, resulting in less binding of von Willebrand factor to platelet receptors [6, 18, 19]. Recent studies [10, 16, 20] suggest that at least two types of ADP receptors exist. The first is a low-affinity type 2 purinergic receptor that is coupled with G proteins and results in the mobilization of calcium from internal stores [21]; this leads to a conformational change in and activation of the glycoprotein IIb/IIIa receptor complex, fibrinogen binding, and platelet aggregation. The second type of ADP receptor (P2Y1) has high affinity and is responsible for platelet shape change and rapid calcium influx [21, 22]. Ticlopidine and clopidogrel do not affect shape change or calcium influx; they seem to achieve their effect by interacting with the low-affinity type 2 purinergic receptor [10, 16, 20]. This interference with a specific ADP-dependent step of glycoprotein IIb/IIIa complex activation results in less platelet aggregation and, thus, ultimately impairs thrombus formation [16, 23, 24]. Despite these numerous in vitro studies, however, the mechanisms of action of ticlopidine and clopidogrel are still not fully characterized. Further insights would be greatly facilitated by the cloning of the type 2 purinergic ADP receptor.

    Figure 2. When vascular endothelial cells are damaged, platelets bind to exposed collagen via glycoprotein (GP) Ib/IX receptors complexed to von Willebrand factor. These bound platelets undergo degranulation, releasing adenosine 5′-diphosphate (ADP). The platelets also release numerous other substances, such as thromboxane A , serotonin, and epinephrine, which play a role in the recruitment and aggregation process. The released ADP binds to two types of receptors, a low-affinity type 2 purinergic receptor and a high-affinity purinergic receptor (P2Y1). Ticlopidine and clopidogrel achieve their antiplatelet effect by blocking the binding of ADP to the type 2 purinergic receptor and preventing the activation of the GP IIb/IIIa receptor complex and subsequent platelet aggregation.
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    Figure 2. When vascular endothelial cells are damaged, platelets bind to exposed collagen via glycoprotein (GP) Ib/IX receptors complexed to von Willebrand factor. These bound platelets undergo degranulation, releasing adenosine 5′-diphosphate (ADP). The platelets also release numerous other substances, such as thromboxane A , serotonin, and epinephrine, which play a role in the recruitment and aggregation process. The released ADP binds to two types of receptors, a low-affinity type 2 purinergic receptor and a high-affinity purinergic receptor (P2Y1). Ticlopidine and clopidogrel achieve their antiplatelet effect by blocking the binding of ADP to the type 2 purinergic receptor and preventing the activation of the GP IIb/IIIa receptor complex and subsequent platelet aggregation. Mechanism of action of ticlopidine and clopidogrel.2

    The inhibition of platelet aggregation by ticlopidine and clopidogrel is concentration-dependent. Significant inhibition is present after 2 to 3 days of therapy with ticlopidine, 500 mg/d, or clopidogrel, 75 mg/d [4, 25]. Maximal inhibition takes 4 to 7 days to achieve, and higher doses do not result in further platelet impairment [4, 25]. One coronary stenting study showed that ticlopidine provides 20% to 30% platelet inhibition when measured by using 20 µmol of ADP per L [26]. In comparison, the currently used doses of glycoprotein IIb/IIIa inhibitors typically achieve 80% to 90% platelet inhibition [27, 28]. The platelet inhibition induced by ticlopidine and clopidogrel seems to be irreversible: The antiplatelet action persists for 7 to 10 days after therapy is stopped; this time course corresponds to the lifespan of a circulating platelet. Of note, a few studies have shown that concomitant aspirin use results in a synergistic inhibition of platelet aggregation that seems to be a consequence of the potentiation of aspirin's effect on collagen-induced platelet aggregation [29-31].

    The observed delay in the inhibition of platelet aggregation is not well understood. It may occur because these agents interfere with megakaryocytopoiesis in addition to impairing the function of circulating platelets [32]. However, recent data from animal studies suggest that ticlopidine can evoke a very rapid antithrombotic response. This effect may explain the clinical response-more rapid than would have been predicted on the basis of the time course of ticlopidine's metabolism-seen in some trials [33]. Another study showed that adding aspirin to ticlopidine after coronary stenting led to a substantial reduction in ADP-induced platelet activation as early as 2 days after initiation of therapy [32]. Although both ticlopidine and clopidogrel prevent platelet aggregation evoked by shear stress [34-37], recent experimental studies suggest that clopidogrel is more effective than either aspirin or ticlopidine in preventing the high shear stress-dependent coronary stent thrombosis [38, 39].

    Ticlopidine and clopidogrel also prolong bleeding time approximately twofold [7, 25]. This prolongation begins immediately after administration, although the maximal effect occurs 5 to 6 days later [5, 40]. The bleeding time returns to normal approximately 10 days after therapy is stopped; again, this corresponds to the lifespan of a platelet. Data on whether ticlopidine reduces erythrocyte aggregability [41], blood viscosity [5, 9, 42, 43], and fibrinogen [5, 40, 43-48] are conflicting. Of note, ticlopidine and clopidogrel have no effect on the cyclooxygenase pathway and therefore act independently of aspirin. No published data are available on any interaction between either of these two agents and glycoprotein IIb/IIIa inhibitors, but preliminary, unpublished data suggest that the combination of ticlopidine and long-term use of oral glycoprotein inhibitors results in increased platelet inhibition.

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    Clinical Applications

    Secondary Prevention of Stroke and Transient Ischemic Attack

    The double-blind Canadian American Ticlopidine Study (CATS) [49] randomly assigned 1072 patients with recent thromboembolic stroke to receive either ticlopidine, 250 mg twice daily, or placebo. At an average follow-up of 2 years, the ticlopidine group had a significant 23.3% reduction in the combined end point of stroke, myocardial infarction, or vascular death compared with the placebo group (11.3% per year compared with 14.8% per year; P = 0.02) (Table 1 and Table 4). The major weakness of this study was the lack of comparison between ticlopidine and aspirin.

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    Table 1. Randomized Clinical Trials of Ticlopidine and Clopidogrel*
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    Table 4. ( ). Table 1Continued

    The Ticlopidine Aspirin Stroke Study (TASS) [50] addressed this question, randomly assigning 3069 patients with recent transient ischemic attack or minor stroke to receive ticlopidine, 250 mg twice daily, or high-dose aspirin, 625 mg twice daily. At 3 years, the ticlopidine group had a 12% reduction in the primary end point of nonfatal stroke or death from any cause compared with the aspirin group (17% compared with 19%; P = 0.048) (Table 1 and Table 4). Most of this reduction was attributable to a 21% reduction in all strokes with ticlopidine (10% compared with 13%; P = 0.024). A subsequent secondary analysis also showed a significant reduction in recurrent transient ischemic attacks with ticlopidine (30% compared with 43%; P = 0.007) [51].

    The recently reported Ticlopidine Indobufen Stroke Study (TISS) [52] was an open trial that randomly assigned 1632 patients with recent transient ischemic attack, amaurosis fugax, or minor stroke to receive ticlopidine, 250 mg/d, or indobufen (a nonsteroidal anti-inflammatory drug), 200 mg/d. The ticlopidine group had a 50% reduction in the primary end point of death, stroke, or myocardial infarction compared with the indobufen group (2.9% compared with 5.8%; P = 0.004) (Table 1 and Table 4).

    On the basis of the TASS and CATS data, the FDA approved ticlopidine for persons who do not respond to or cannot tolerate aspirin [53]. However, because of the risk for neutropenia seen with ticlopidine, aspirin remains the first-line agent for patients with a history of transient ischemic attack or stroke.

    Peripheral Arterial Obliterative Disease

    In the Swedish Ticlopidine Multicentre Study (STIMS) [54], 687 patients with intermittent claudication were randomly assigned to receive ticlopidine, 250 mg twice daily, or placebo. In the intention-to-treat analysis, the ticlopidine group had a statistically insignificant reduction of 11.4% in the combined end point of myocardial infarction, stroke, and transient ischemic attack (Table 1 and Table 4). Among patients actually receiving treatment, the ticlopidine group had a significant reduction in events (13.8% compared with 22.4%; P = 0.017) and lower all-cause mortality (18.7% compared with 26.1%; P = 0.015).

    A second study [55] found that ticlopidine (250 mg twice daily without aspirin) reduced major events (transient ischemic attack, cerebrovascular accident, and peripheral ischemic attacks requiring surgical intervention) by 77% at 6 months compared with placebo [55] (Table 1 and Table 4). A more recent trial [56] enrolling 615 patients used the same design (ticlopidine, 250 mg, compared with placebo) and confirmed these findings with a 75% reduction at 6 months in the combined end point of death, myocardial infarction, stroke, and cardiovascular intervention related to clinical deterioration (Table 1 and Table 4).

    Unstable Angina and Myocardial Infarction

    Only one randomized trial has examined the use of ticlopidine in patients with unstable angina [57]. This study enrolled 652 patients within 48 hours of admission and randomly assigned them to receive 1) conventional therapy, which consisted of calcium-channel antagonists, β-blockers, nitrates, or some combination of these three agents, or 2) conventional therapy plus ticlopidine, 250 mg twice daily. Conventional therapy did not include aspirin because when the trial was designed, aspirin was not routinely used to treat patients with unstable angina. At 6 months of follow-up, the ticlopidine group had a significant 46% reduction in the primary combined end point of vascular death and nonfatal myocardial infarction (7.3% compared with 13.6%; P = 0.009). Of note, no difference in the number of events was seen over the first 10 days; this finding is consistent with the delayed onset of the antiplatelet effect of ticlopidine.

    Symptomatic Atherosclerosis

    The Clopidogrel versus Aspirin in Patients at Risk for Ischemic Events (CAPRIE) trial [58] studied patients with symptomatic atherosclerosis, which was defined as recent ischemic stroke (within 1 week to 6 months), myocardial infarction (within 35 days), or documented peripheral arterial disease. More than 19 000 patients were randomly assigned to receive either clopidogrel, 75 mg once daily, or aspirin, 325 mg once daily; mean follow-up was 1.9 years. Overall, clopidogrel was associated with a significant 8.7% reduction compared with aspirin in the primary end point of ischemic stroke, myocardial infarction, or vascular death (5.32% compared with 5.83% per year; P = 0.043). On the basis of these data, the FDA recently approved clopidogrel for the secondary prevention of vascular events in patients with symptomatic atherosclerosis. Future studies are planned to evaluate the combination of aspirin plus clopidogrel.

    Of note, unexplained heterogeneity was seen among the three CAPRIE entry criteria groups (test for heterogeneity, P = 0.042). The patients with peripheral arterial disease showed significantly greater benefit with clopidogrel than with aspirin (3.71% per year compared with 4.86% per year; P = 0.0028), the stroke group had less benefit (7.15% per year compared with 7.71% per year; P > 0.2), and the myocardial infarction group had a nonsignificant 3.7% increase in events (5.03% per year compared with 4.84%; P > 0.2). In a post hoc secondary analysis of all patients with previous myocardial infarction (2144 additional patients from the peripheral arterial disease and stroke strata who had a history of myocardial infarction), clopidogrel was associated with a 7.4% decrease in the combined end point. Another analysis of all 19 185 enrolled patients showed that clopidogrel had more benefit in the prevention of myocardial infarction than it did in the prevention of the other components of the primary end point; a statistically significant 19.2% reduction in myocardial infarction (5.2% compared with 7.6%; P = 0.008) and nonsignificant reductions of 5.2% in stroke and 7.6% in vascular death were seen [66]. Future studies enrolling only patients with acute myocardial infarction will better define the role and efficacy of clopidogrel in this patient population.

    Prevention of Coronary Artery Stent Thrombosis

    The early experience with coronary stenting was notable for high rates of subacute stent thrombosis, a complication that is difficult to treat and frequently results in myocardial infarction or death [67-69]. Despite antithrombotic regimens using several agents, including aspirin, dipyridamole, dextran, heparin, and warfarin [70, 71], reported rates of stent thrombosis ranged from 6% to 20% in these early studies [69, 72-75]. Such aggressive regimens also led to frequent bleeding complications and prolonged hospitalization [76-79]. With significant stent thrombosis occurring in the face of systemic bleeding, it was clear that more effective antithrombotic regimens were necessary.

    Initial nonrandomized studies added ticlopidine, 250 mg twice daily, for 1 month to a postprocedural regimen of aspirin and heparin or low-molecular-weight heparin. A total of 1251 patients in a French multicenter registry received ticlopidine, and the use of this agent led to a reduction in stent thrombosis from 10.4% to between 1.3% and 1.8% [80]. This simplified regimen was associated with two-thirds fewer bleeding complications (Table 2).

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    Table 2. Bleeding Complications and Subacute Stent Thrombosis in Coronary Stenting Regimens

    A subsequent nonrandomized study used only oral antiplatelet agents [81]. A total of 321 patients who had adequate stent expansion after high-pressure balloon inflation verified by intravascular ultrasonography received either ticlopidine, 250 mg twice daily, for 1 month and aspirin, 325 mg once daily, for 5 days or aspirin alone for 1 month. At 6 months of follow-up, the stent thrombosis rate was only 0.8% in the group treated with aspirin and ticlopidine and 1.4% in the group treated with aspirin alone (a nonsignificant difference). Although these rates were significantly lower than those in historical controls and suggested the efficacy of the new antiplatelet regimen, this was not a randomized study. Thus, the lower thrombosis rates may have been due to use of the new high-pressure balloon technique [82, 83] or other uncontrolled variables, such as increasing operator experience.

    The first randomized trial (ISAR [Intracoronary Stenting and Antithrombotic Regimen]) [59] confirmed the advantage of an antiplatelet regimen over an anticoagulant regimen. A total of 517 patients were randomly assigned to receive 1) intravenous heparin for 12 hours; ticlopidine, 250 mg twice daily for 4 weeks; and aspirin, 100 mg twice daily for 4 weeks or 2) intravenous heparin for 5 to 10 days; aspirin, 100 mg twice daily for 4 weeks; and phenprocoumon (target international normalized ratio [INR], 3.5 to 4.5) for 4 weeks. At 30 days of follow-up, the ticlopidine group had 75% fewer cardiac end points than the phenprocoumon group (1.6% compared with 6.2%; P < 0.001) and had had no episodes of stent thrombosis (compared with 5.0%; P < 0.001) (Table 2). These reductions remained significant at 6 and 12 months of follow-up [84].

    A larger, adequately powered study [60] has shown an impressive benefit of a ticlopidine-containing regimen compared with both anticoagulation and aspirin-only regimens. The Stent Antithrombotic Regimen Study [STARS] randomly assigned 1653 patients to receive 1) aspirin, 325 mg once daily, plus warfarin [target INR, 2.0 to 2.5]; 2) aspirin plus ticlopidine, 250 mg twice daily; or 3) aspirin alone for 1 month. Preliminary results show a reduction greater than 80% at 30 days in the combined end point of death, Q-wave myocardial infarction, emergency surgery, target vessel revascularization, and angiographic thrombosis in the ticlopidine-aspirin group compared with the other treatment groups (0.5% compared with 2.7% for aspirin plus warfarin [P = 0.007] and 3.6% for aspirin only [P < 0.001]) (Table 1 and Table 4).

    Whether ticlopidine is necessary for all patients or all types of coronary stents is not yet established. Two studies [61, 85], including a randomized trial enrolling 226 patients, have shown the superiority of a ticlopidine-aspirin regimen compared with aspirin alone. Other, nonrandomized studies have reported that aspirin alone or ticlopidine alone may be adequate [86-88]. Preliminary data suggest that patients at high risk for stent thrombosis, such as those with complex lesions, small target vessel diameters (<3 mm), and residual dissection after stenting, benefit the most from combination antiplatelet therapy with aspirin and ticlopidine [87-91].

    Most centers now administer ticlopidine before anticipated stenting procedures. Recent pilot studies suggest that starting ticlopidine therapy 1 to 3 days before coronary stenting minimizes thrombotic complications, presumably by establishing a significant level of platelet inhibition at the time of stenting [92, 93]. Many centers are also reducing the duration of treatment to 10 to 14 days because most episodes of stent thrombosis occur early after stent placement. In STARS, these episodes occurred at a mean of 0.7 days [60, 94-96].

    Several studies have addressed the use of ticlopidine in the expanding number of clinical settings for which stents are used, such as chronic total coronary occlusions [82, 97]; saphenous vein graft disease [71, 97-100]; and, more recently, acute myocardial infarction [101-105]. Preliminary reports from several groups indicate that ticlopidine is beneficial for all of these indications [106-109]. In addition, numerous new stent designs [109], coated stents [110], and radiation therapy after stenting [111] have shown promise in initial studies. Ticlopidine has been given concomitantly with short-term administration of intravenous abciximab, a glycoprotein IIb/IIIa inhibitor [26], but its use in conjunction with long-term administration of these potent antiplatelet agents requires study.

    Other Uses

    Several studies have examined the efficacy of ticlopidine in maintaining the patency of saphenous vein grafts and preventing restenosis. A study of patients undergoing coronary artery bypass surgery randomly assigned 77 patients to receive ticlopidine, 250 mg twice daily, started 3 days before surgery, or placebo; saphenous vein graft patency was evaluated at 3 months by coronary angiography and thallium imaging [62]. The ticlopidine group had a statistically insignificant 50% reduction in graft occlusion (10.1% compared with 20.3%); however, on-treatment analysis showed a significant 67% reduction in occlusion rates (7.1% compared with 21.8%; P < 0.02). A second study by the same group [63], which randomly assigned 173 patients undergoing coronary artery bypass grafting to receive ticlopidine, 250 mg twice daily, from the second postoperative day on or placebo for up to 12 months, showed significant reductions with ticlopidine in graft occlusion at postoperative days 10, 180, and 360 (P < 0.05 for all comparisons). A recent randomized study [64] examined the use of ticlopidine, 250 mg twice daily, or placebo in patients with femoropopliteal or femorotibial saphenous vein grafts. At 2 years of follow-up, graft patency was better with ticlopidine than with placebo (82% compared with 63%; P = 0.002).

    One study [65] has examined the effect of ticlopidine in patients with diabetic retinopathy. The Ticlopidine Microangiopathy of Diabetes (TIMAD) study randomly assigned 435 patients with nonproliferative diabetic retinopathy to receive ticlopidine, 250 mg twice daily, or placebo. At 3 years of follow-up, the ticlopidine group had a significant reduction in overall disease progression (P = 0.04) and a seven-fold reduction in annual microaneurysm progression (P = 0.03). A recent study of patients undergoing radiofrequency catheter ablation showed 40% lower d-dimer levels in patients who were pretreated for 3 days with ticlopidine and aspirin [112]. Finally, the preliminary results of a study addressing the prevention of reocclusion after coronary angioplasty showed a benefit with ticlopidine plus aspirin compared with aspirin alone [113]; another, similar study showed no advantage for ticlopidine plus aspirin [114].

    Side Effects

    A major side effect of ticlopidine and clopidogrel, like all antithrombotic agents, is bleeding. However, experience to date has shown very low rates of major hemorrhage with the use of ticlopidine in stent trials. With the elimination of dextran, warfarin, prolonged infusions of intravenous heparin, and low-molecular-weight heparin from post-stenting regimens, the incidence of bleeding has decreased significantly (from between 3% and 7% to <2%). Further evidence of the low bleeding rates associated with ticlopidine is seen in the secondary stroke prevention trials. In TASS, the rate of major hemorrhage was 0.5% with ticlopidine and 1.4% with aspirin (P < 0.05) [50, 51]. The rates of minor bleeding were similar with the two treatments (9% compared with 10%). In CATS, the ticlopidine and placebo groups had a similar incidence of major bleeding (0.2% compared with 0.4%), although ticlopidine-treated patients had twice as many minor bleeding episodes (6.5% compared with 3.0%; P value not reported) [49]. Clopidogrel is also infrequently associated with severe bleeding. In the large CAPRIE trial [58], major hemorrhage occurred in 1.4% of clopidogrel-treated patients; this percentage was not significantly different from that seen in aspirin-treated patients (1.6%).

    Ticlopidine can result in neutropenia, a side effect that can be fatal because of the associated increased risk for serious infection [49, 50, 115, 116]. In TASS [50], neutropenia (absolute neutrophil count < 1200 cells/mm3) occurred in 2.4% and severe neutropenia (absolute neutrophil count < 450 cells/mm3) occurred in 0.9% of patients receiving ticlopidine compared with 0% of patients receiving aspirin. In CATS, severe neutropenia (absolute neutrophil count < 450 cells/mm3) was seen in 0.8% of patients [49]. In the largest two coronary stenting trials (the ISAR study and STARS), the rates of neutropenia in the ticlopidine groups did not differ from those in the control groups (0.5% compared with 0% in the ISAR study and 0.2% compared with 0% in STARS); this is probably due to the limited 1-month duration of therapy. Neutropenia typically occurs in the first few months after initiation of therapy, but it is seen infrequently in the first 2 to 3 weeks. It is recommended that blood counts be checked every 2 weeks for at least the first 3 months of therapy [4, 117]. In most, but not all, cases, the neutropenia resolves with cessation of drug administration [49, 54, 118]. Clopidogrel was developed because it did not show bone marrow toxicity in tissue culture and animal models. In the large CAPRIE trial, the incidence of severe neutropenia with clopidogrel was only 0.1%; this was similar to the rate seen with aspirin (0.17%) [58]. Another serious and often fatal side effect of ticlopidine is thrombotic thrombocytopenic purpura [50, 117-125]. A recent review [123] documented 60 cases of thrombotic thrombocytopenic purpura seen among patients treated with ticlopidine worldwide; the associated mortality rate was 33%. Only 2 of the 60 cases occurred after less than 2 weeks of ticlopidine administration; this further supports the relative safety of shorter therapy after coronary stenting.

    Other adverse effects reported to accompany ticlopidine use are gastrointestinal symptoms: diarrhea (in ≥ 20% of patients), nausea, dyspepsia, and anorexia [49, 50, 54, 64]. In TASS [50], more ticlopidine-treated patients than aspirin-treated patients discontinued therapy because of diarrhea (6% compared with 2%) and rash (3% compared with 1%). Diarrhea is often related to failure to take the medication with adequate food or with meals. Gastrointestinal side effects usually occur during the first 2 to 3 weeks of ticlopidine administration. Ticlopidine has also been reported to result in higher total serum cholesterol levels; in TASS, an average increase of 9% was seen [50]. In the large CAPRIE trial, clopidogrel was not associated with any changes in cholesterol levels [58].

    Other side effects of ticlopidine and clopidogrel include pruritus, urticaria, hemorrhage (gastrointestinal and intracranial), ecchymoses, and epistaxis (Table 3). With clopidogrel, these adverse effects seem to occur less often, and most of the reactions are mild and resolve with discontinuation of therapy [58]. Less common adverse effects that have been reported with ticlopidine include thrombocytopenia [115, 126], aplastic anemia [127, 128], severe cholestasis [129, 130], hepatitis [131], and acute interstitial nephritis [132, 133]. Women older than 75 years of age seem most likely to develop hematologic side effects [115].

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    Table 3. Side Effects of Ticlopidine and Clopidogrel

    Clearance of ticlopidine and clopidogrel is affected by certain medications. In particular, the clearance of ticlopidine is reduced by 50% with concomitant cimetidine use [134]. Ticlopidine has also been shown to affect the metabolism of some medications. Doses of cyclosporine may need to be increased [135, 136], whereas doses of theophylline, carbamazepine, and phenytoin may need to be reduced [137-140] when these drugs are used concomitantly with ticlopidine.

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    Conclusions

    Among patients undergoing coronary artery stenting, the use of ticlopidine in conjunction with aspirin is recommended to minimize the risk for stent thrombosis and major cardiac complications. Longer-term use of ticlopidine has shown benefit in secondary prevention of stroke, peripheral vascular disease, and unstable angina, but it is associated with a significant risk for severe neutropenia. Ticlopidine use has therefore been limited to patients who are aspirin-intolerant and, in some instances, to patients in whom aspirin therapy has failed.

    The side effect profile of the newer and now FDA-approved antiplatelet agent clopidogrel is better than that of ticlopidine and similar to that of aspirin. One large secondary prevention study among patients with recent myocardial infarction, stroke, or peripheral vascular disease has shown that clopidogrel reduces the overall rate of stroke, myocardial infarction, and vascular death compared with aspirin and is associated with the same risk for neutropenia (approximately 0.1%). Future studies need to define the role of clopidogrel for coronary stenting and other indications as well as the effect of clopidogrel in combination with aspirin. Finally, clopidogrel and ticlopidine cost significantly more than aspirin (cost to hospital, $1 to $3 compared with <$0.01 per tablet); thus, thorough cost-effectiveness analyses need to be done to determine whether significant clinical benefit is obtained at a reasonable cost.

    Numerous oral glycoprotein IIb/IIIa inhibitors are being studied for similar indications [141, 142]. Any reduction in ischemic events seen with these potent antiplatelet agents may be accompanied by an increased risk for bleeding. These risk–benefit profiles must be compared with those seen to date for ticlopidine and clopidogrel. Direct comparisons of clopidogrel and glycoprotein IIb/IIIa inhibitors in future randomized trials will provide the most definitive comparative safety and efficacy data. Currently, ticlopidine and clopidogrel are the available, newer antiplatelet agents. Studies show that these drugs have beneficial effects consistent with those of aspirin in a broad range of patients, highlighting the importance of antiplatelet therapy in cardiovascular disease.

    Dr. Loscalzo: Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, 88 East Newton Street, Boston, MA 02118-2394.

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    1. Ann Intern Med September 1, 1998 vol. 129 no. 5 394-405
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