Cilostazol-based triple antiplatelet therapy in the era of generic clopidogrel and new potent antiplatelet agents

Keywords::

• Cilostazol
• Indirect comparison
• Meta-analysis
• Percutaneous coronary intervention
• Triple antiplatelet therapy

Platelet activation plays a pivotal role in the pathogenesis of atherothrombosis and the development of ischemic complications during acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI)1–4. Thromboxane A₂ (TxA₂) and adenosine diphosphate (ADP) are two major platelet agonists that are released from activated platelets, thus enhancing platelet activation, and promoting the formation of stable thrombus at the site of vascular injury1,5. Therefore, the pharmacologic management of coronary artery disease patients with high thrombotic risk consists of the inhibition of TxA₂ synthesis with the cyclooxygenase-1 inhibitor aspirin, and blockade of the ADP-receptor P2Y12 with specific antagonists clopidogrel, prasugrel or ticagrelor5. The combination of aspirin with one of the above ADP-receptor antagonists is known as dual antiplatelet therapy (DAT)5. DAT with aspirin and clopidogrel became the gold standard treatment of ACS patients as well as those undergoing PCI since its beneficial effect in reducing the incidence of stent thrombosis and major adverse cardiovascular events (MACEs) compared with aspirin alone is well established6–8. Indeed, in the CURE (Clopidogrel in Unstable angina to prevent Recurrent ischemic Events) trial, the combination of aspirin and clopidogrel produced additive effects in patients with non-ST-elevation ACS, by reducing the rate of the first primary outcome, a composite of cardiovascular death, non-fatal myocardial infarction (MI), or stroke, from 11.4 to 9.3% (RR, 0.80; 95% CI, 0.72–0.90, P < 0.001) when compared with aspirin alone6. Furthermore, the PCI-CURE study, a subgroup analysis of the CURE trial, demonstrated a 1.9% absolute risk reduction (P = 0.03) in adverse cardiovascular events at 30 days and a 3.4% absolute risk reduction at 9 months in the clopidogrel loading arm, favoring long-term use of DAT7. These results were further supported by the CREDO (Clopidogrel for the Reduction of Events During Observation) trial8 in which long-term DAT in 2116 patients with coronary artery disease undergoing elective PCI resulted in a 3% absolute risk reduction and a 26.9% relative risk reduction (P = 0.02) in death, MI, or stroke8.

More recent studies have demonstrated that, despite DAT, up to 20% of patients experience recurrent ischemic events and this has been primarily attributed to hyporesponsiveness (resistance) to aspirin or to clopidogrel9–15. Most of the studies have been focused on clopidogrel hyporesponsiveness (high on-treatment platelet reactivity, HTPR)11–13, which has been observed using a variety of laboratory methods5,15,16. Although the mechanisms underlining clopidogrel hyporesponsiveness to antiplatelet treatment are likely to be multifactorial5,15,16, HTPR has been mostly attributed to abnormalities of clopidogrel metabolism. Indeed, under physiological conditions, only 15% of intestinally absorbed clopidogrel prodrug undergoes activation in the liver into thiol metabolite by the hepatic cytochrome P-450 (CYP) enzymatic pathway5,16. This clopidogrel metabolic activation involves several CYP isoenzymes, including CYP2C19, CYP3A4/5, CYP2C9, CYPP1A2 and CYP2B6^5,16. It has been well established that the existence of the loss of function CYP2C19 alleles (*2, *3, *4, *5, *6, *7 and *8), especially the CYP2C19*2 allele, are associated with a lower rate of clopidogrel metabolic activation and attenuate its pharmacodynamic effect and clinical efficacy5,16. This variability to clopidogrel response is clinically important since HTPR is a risk factor for MACEs, particularly stent thrombosis after PCI13–16. Thus, overcoming HTPR and optimizing antiplatelet therapy in patients post-PCI remains an important goal for the interventional cardiologist. Cilostazol is a quinolinone derivative that selectively and reversibly inhibits cellular cyclic adenosine monophosphate (cAMP) phosphodiesterase III, thus suppressing cAMP degradation17. As a result it increases cAMP concentrations in blood vessels and platelets, inducing peripheral vasodilatation and reversibly inhibiting platelet aggregation17. Furthermore, cilostazol exerts pleiotropic effects, since it may improve atherogenic dyslipidemia in high-risk patients18. It also inhibits neointimal hyperplasia and smooth muscle proliferation after endothelial injury thus, in addition to its antiplatelet effects, cilostazol may prevent restenosis, an unresolved issue following PCI, even in the drug-eluting stent era17. Consequently, adding cilostazol to aspirin plus clopidogrel (triple antiplatelet therapy, TAT) may represent an effective way to overcome HTPR. In the ACCEL-AMI (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With AMI) study, cilostazol-based TAT in patients with acute MI undergoing coronary stenting, achieved greater inhibition of ADP-induced platelet aggregation at 30 days compared with a high clopidogrel maintenance dose (150 mg daily) or standard DAT19. Similarly, adjunctive cilostazol in acute MI patients enhances inhibition of ADP-induced platelet aggregation, compared with a high clopidogrel maintenance dose (150 mg daily), especially in those with CYP2C19 loss of function variants (*2/*3)20. Furthermore, the randomized ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) study demonstrated that in patients with HTPR undergoing coronary stenting, adjunctive cilostazol reduces the rate of HPPR and intensifies platelet inhibition compared with a high clopidogrel maintenance dose (150 mg daily)21. In accordance with the results of the above studies are those of a recent meta-analysis which included nine studies involving 2179 patients undergoing PCI, with the aim of comparing the efficacy of cilostazol-based TAT versus DAT in regard to on-treatment platelet reactivity. This meta-analysis concluded that TAT significantly lowers platelet reactivity suggesting that it may be more effective than DAT in reducing the thrombotic complications following PCI22.

In addition to its antiplatelet efficacy, cilostazol-based TAT can also reduce restenosis following PCI23,24. A recent study that included data from three randomized trials (DECLARE-DIABETES; Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients With Diabetes Mellitus as well as DECLARE-LONG I and II; Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients With Long Native Coronary Lesions) evaluated the antirestenotic efficacy of TAT according to the implanted drug-eluting stent, in patients at high restenosis risk25. A total of 1399 patients who underwent implantation of sirolimus-eluting stent (SES; n = 450), paclitaxel-eluting stent (n = 450), and zotarolimus-eluting stent (n = 499), received either cilostazol-based TAT (n = 700) or conventional DAT (n = 699). In-stent late loss after TAT was significantly lower than that after DAT, regardless of implanted stent type. However, the incidence of in-segment restenosis after TAT was significantly lower with SES (0.5 vs 6.7%, P = 0.014) and zotarolimus-eluting stent implantation (12.2 vs 20.0%, P = 0.028) but not paclitaxel-eluting stent implantation (14.4 vs 20.0%, P=0.244), suggesting that TAT exhibits a potent antirestenotic effect in patients at high risk for restenosis, particularly in those receiving SES25.

The article by Chen et al. published in the present issue of Current Medical Research and Opinion is the largest meta-analysis performed to date on the long-term clinical efficacy and safety of adding cilostazol to standard DAT in patients undergoing PCI26. In the same study the authors also performed adjusted indirect comparisons of cilostazol-based TAT versus new generation of oral ADP-receptor antagonist (prasugrel or ticagrelor) based DAT. These new antiplatelet drugs have gained considerable attention, since large randomized controlled trials such as TRITON–TIMI 38²7 and PLATO28 demonstrated that prasugrel and ticagrelor, respectively, were superior to clopidogrel for prevention of ischemic events in ACS patients with scheduled PCI27,28. Twelve randomized controlled trials with a total of 31,789 patients comparing TAT versus standard DAT or prasugrel/ticagrelor based DAT were included in this meta-analysis26. The authors established strict inclusion criteria including cilostazol daily dose of no less than 200 mg and duration of drug administration and follow-up ≥6 months. The primary efficacy end-points were the incidence of MACEs defined as composite events of cardiovascular death, stent thrombosis, MI or repeat revascularization. Target lesion revascularization (TLR), target vessel revascularization (TVR), death, MI and stent thrombosis were the secondary efficacy end-points. Major bleeding was the primary safety end-point, whereas overall bleeding, rash, headache and gastrointestinal disorders were considered as secondary safety end-points. Compared with standard DAT, TAT significantly reduced the incidence of MACEs (OR: 0.56, 95% CI: 0.47–0.68, P < 0.00001), TLR (OR: 0.51, 95% CI: 0.34–0.75, P = 0.0006) and TVR (OR: 0.59, 95% CI: 0.46–0.75, P < 0.0001). However, TAT and standard DAT did not differ significantly in death, MI or stent thrombosis26. Importantly, TAT did not increase the incidence of bleeding complications including major bleeding and overall bleeding compared with standard DAT; however, it increased other adverse events including rash (OR: 2.92, 95% CI: 1.86–4.59, P < 0.00001), headache (OR: 4.80, 95% CI: 2.28–10.11, P < 0.0001) and gastrointestinal disorder (OR: 2.25, 95% CI: 1.39–3.63, P = 0.0009)26.

Adjusted indirect comparison of TAT with prasugrel or ticagrelor based DAT demonstrated that TAT further reduces the incidence of MACEs (OR: 0.70, 95% CI: 0.56–0.87, z = −3.24, P = 0.0012 for prasugrel; OR: 0.67, 95% CI 0.55–0.83, z = −3.65, P = 0.0003 for ticagrelor). However, TAT failed to reduce the incidence of death, MI and stent thrombosis, which could be ameliorated by prasugrel or ticagrelor based DAT compared with standard DAT26–28.

In conclusion cilostazol is an important and useful drug since it inhibits platelet activation and could also prevent restenosis. The present meta-analysis26 clearly demonstrates that the long-term use of cilostazol-based TAT in patients undergoing PCI exhibits higher efficacy compared with standard DAT in reducing the incidence of MACEs, TLR and TVR, without increasing the incidence of major and overall bleeding. These results are of particular importance considering that despite the availability of the new potent antiplatelet agents, prasugrel and ticagrelor, clopidogrel is still widely used and currently is a low cost drug due to approval of many generic clopidogrel formulations, most of which exhibit comparative pharmacodynamic effectiveness and clinical efficacy with the original drug29,30. It should be emphasized that cilostazol-based TAT has predominantly been studied in Koreans, a population with a high prevalence of loss of function CYP2C19 alleles, which is associated with HTPR and significantly diminished clopidogrel clinical efficacy. Consequently the results of the present meta-analysis26 in concert with those of previous studies21,22 strongly support the suggestion that addition of cilostazol to standard therapy with aspirin and clopidogrel is an effective way to overcome HTPR and improve clinical outcomes, especially in patients undergoing PCI, without increasing bleeding. However, TAT did not further reduce the incidence of death, MI or stent thrombosis compared with standard DAT and this is contradictory to the pharmacodynamic properties of cilostazol17. Thus, future studies in large and diverse populations aiming to compare the clinical efficacy of cilostazol-based TAT versus standard DAT in reducing the incidence of stent thrombosis MI and death are necessary. The present meta-analysis further showed that, compared with prasugrel or ticagrelor based DAT, TAT may be superior in reducing the recurrence of MACEs; however, it failed to reduce the incidence of death, MI and stent thrombosis among patients undergoing PCI. It should be stated however that these conclusions are drawn through adjusted indirect comparisons, which may not overcome intrinsic limitations and unknown confounding factors. Furthermore, it may be considered that TRITON–TIMI 38 and PLATO were mainly performed in Western countries (white race above 90%) while all TAT trials were conducted in East Asia. In a recent study, the peri-procedural inhibition of platelet aggregation by prasugrel in clopidogrel-naive patients with STEMI undergoing primary PCI was compared with cilostazol-based TAT31. The authors showed that prasugrel induces a significantly greater peri-procedural as well as in-hospital inhibition of platelet aggregation compared with TAT31. Thus, future studies with direct comparisons in large and diverse populations between cilostazol-based TAT and prasugrel or ticagrelor based DAT are necessary to validate the potential benefits of cilostazol in PCI compared with the new potent antiplatelet agents.

Transparency

Declaration of funding

The author received no funding in preparation of this manuscript.

Declaration of financial/other relationships

A.D.T. has received consulting and speaker fees as well research grants from AstraZeneca Hellas, Bayer Hellas ABEE, Boehringer Ingelheim Hellas SA, Bristol Myers Squibb AE, Elpen and Pfizer Hellas SA.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.