Ticlopidine [5-(2-chlorophenyl)methyl-4,5,6,7-tetrahydrothieno[3,2-c] pyridine], a first-generation thienopyridine, is an oral antagonist of the adenosine diphosphate (ADP) receptor, which acts by irreversible blockade of the P2Y₁₂ platelet surface receptor [10]. Ticlopidine does not inhibit ADP-induced platelet aggregation in vitro, because it is a prodrug that requires hepatic biotransformation into an active metabolite [11]. Thirteen metabolites have been described and cytochrome P450 (CYP)2C19 and CYP2B6 are known to be involved in ticlopidine metabolism. However, the complete metabolic pathway producing the active thiolactone, which binds irreversibly the P2Y₁₂ receptor by generation of 2-oxo-ticolpidine, is still unclear (Figure 18.1) [12].

The in vivo onset of action after oral administration of ticlopidine (250 mg bid) occurs after 24–48 h, while about 5 days are required to reach maximal ADP-induced platelet inhibition. Approximately 85% of the drug is absorbed and the peak plasma concentration is reached after 2 h from drug intake. Bioavailability is increased by food and decreased by antacids. After repeated dosing, the clearance of ticlopidine decreases significantly, probably due to the inhibition on its own metabolism by inhibiting CYP2C19 and CYP2B6. Elimination of ticlopidine is 60% renal and 23% gastrointestinal. Platelet inhibitory effects are saturated at a dosage of 250 mg twice a day; a single 500 mg daily dose was also tested and showed a faster full inhibitory effect (4 days) but at the expense of more gastrointestinal side effects [7, 13, 14].

Pharmacodynamic profile

To date, few studies have been published on the pharmacodynamic (PD) effects of ticlopidine compared with other thienopyridines. Although platelet inhibition is dose dependent, the relation between the degree of platelet inhibition and plasma concentrations of active metabolites is still unclear [15]. Maximum platelet inhibition occurs 3–5 days after daily administration in healthy subjects, and the offset occurs 3–4 days after discontinuation of 250 mg daily doses and 11–13 days after 500 mg doses [14]. The addition of ticlopidine to aspirin allows reducing platelet reactivity more than what each single drug does [16], even in patients undergoing PCI (ADP (2 μM)-induced platelet aggregation: 36 ± 12 in aspirin plus ticlopidine versus 54 ± 12 in aspirin alone; p < 0.0001) [17]. Same results were found also using vasodilator-stimulated phosphoprotein (VASP), which is an assay specific to evaluate the P2Y₁₂ receptor signaling [18]. PD effects of ticlopidine were also evaluated in patients with chronic kidney disease, but no significant difference compared with healthy volunteers was shown; thus, no dose adjustment is required in patients with impaired renal function [19]. In a study on patients with stable angina scheduled for coronary angiography, the administration of a ticlopidine 1500 mg loading dose showed significantly higher platelet inhibition at 24 h compared to the modest antiplatelet effect achieved by the standard dosage (250 mg twice daily), as assessed by ADP-induced platelet fibrinogen binding. However, at 1 week, no difference was found between the two strategies [20].

Genetic considerations

It is well known that CYP2C19 polymorphisms reduce the antiplatelet effect of clopidogrel and increase the risk of ischemic cardiac events, such as stent thrombosis [21].Ticlopidine is a prodrug metabolized by multiple CYPs, including CYP2C19 as well [11]. However, in vivo production of ticlopidine active metabolites and pharmacokinetic properties do not depend mainly on CYP2C19 activity. Moreover, CYP2C19 polymorphisms did not show to reduce ticlopidine antiplatelet therapy [22]. Maeda et al. demonstrated that ADP (20 µmol/L)-induced platelet aggregation, evaluated by light transmittance aggregometry, was similar in extensive, intermediate, and poor metabolizers (PM), according to CYP2C19 genotypic status. Furthermore, platelet aggregation was significantly lower in PM patients on ticlopidine treatment group than on clopidogrel (33.8% vs. 19.1%; P < 0.001), and in clopidogrel PM that switched to ticlopidine, platelet aggregation was further suppressed (33.4% vs. 17.3%; P < 0.01) [23]. The role of ticlopidine in patients with pharmacological resistance to clopidogrel was tested in a case report series [24]. However, this was more adequately evaluated by Campo et al. who studied 143 patients undergoing PCI for stable coronary artery disease or ST-segment elevation MI [25]. The authors found that patients with resistance to clopidogrel (21%) were mainly responsive to ticlopidine and vice versa. In particular, 83% of patients who were clopidogrel nonresponders resulted to be responsive to ticlopidine, reaching a significant higher level of platelet inhibition (ADP (20 µmol/L)-induced platelet aggregation: 69 ± 15 vs. 44 ± 18; P < 0.05). Only 3.5% of patients (5 of 143) demonstrated both clopidogrel and ticlopidine resistance, suggesting a drug-specific mechanism, rather than a class effect, for thienopyridine resistance.

Clinical efficacy in patients undergoing PCI

Although some studies have assessed the role of ticlopidine in the other settings of vascular disease manifestations [4, 5], ticlopidine has been mostly acknowledged for its impact in the setting of patients undergoing PCI and stenting (Figure 18.2). In fact, despite the introduction of coronary stents in the late 1980s, the optimal antithrombotic treatment regimen to prevent stent thrombosis remained a challenge, hampering the clinical application of stent procedures. The combination of aspirin with anticoagulants was associated with high rates of thrombotic and bleeding complications. Therefore, an approach to achieve synergistic antiplatelet effects by blocking two key pathways, cyclooxygenase-1 with aspirin and the ADP receptor with ticlopidine, introducing the concept of “DAPT,” was approached in four pivotal trials.

The Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial evaluated the effect of ticlopidine after PCI and coronary stenting [26]. Patients (n = 517) were randomized to receive DAPT with aspirin (100 mg twice a day) plus ticlopidine (250 mg twice a day started immediately after the procedure and continued for 4 weeks) or conventional therapy with intravenous heparin, vitamin K antagonist (VKA), and aspirin. The primary cardiac end point was a composite of cardiovascular death, MI, aortocoronary bypass surgery, or repeated PCI of the stented vessel. At a 30-day follow-up, ticlopidine significantly reduced the incidence of the primary end point (1.6% vs. 6.2%; RR, 0.25; 95% CI, 0.06–0.77; p = 0.01) with an 82% reduction of MI. The rate of hemorrhagic events was also reduced in the ticlopidine group (p < 0.001).

In the Full Anticoagulation Versus Aspirin and Ticlopidine (FANTASTIC) study, patients (n = 485) undergoing stent implantation were randomized to receive DAPT with ticlopidine (500 mg loading dose administered immediately after procedure and then 250 mg bid for 6 weeks) plus aspirin (100–325 mg for life) or anticoagulant therapy (heparin and VKA) for 6 weeks plus aspirin [27]. The primary end point, the occurrence of any bleeding or peripheral vascular complications during the 6 weeks after stent implantation, was significantly reduced in the ticlopidine arm (13.5% vs. 21%; OR, 0.59; 95% CI, 0.39–0.98; p

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