Novel antiplatelet agents in the prevention of cardiovascular complications – focus on ticagrelor

Figures & data

Figure 1 Scheme of platelet adhesion, activation, and aggregation processes – showing the key players and sites of action of antiplatelet agents. Drugs at various stages of investigation appear in parentheses.

Abbreviations: AA, arachidonic acid; ADP, adenosine diphosphate; ASA, aspirin; COX, cyclooxygenase; GP, glycoprotein; PAR, protease-activated receptor; PR, thromboxane/prostanoid receptor; TXA₂, thromboxane; vWF, von Willebrand Factor.

Table 1 Pharmacologic properties and adverse effects of a selection of antiplatelet agents

Drug	Action	Aggregation to ADP	Route of administration	Metabolism	Time to peak effect	Offset of action	Adverse effects
Clopidogrel 300 mg	IRR	∼30%	Oral	Esterase inactivation and two-step hepatic CYP-dependent activation	∼4 hours	∼5 days	Bleeding (major and minor), interpatient variability, and dyspnea in approximately 8% of patients^Citation34
Prasugrel 60 mg	IRR	75%–80%	Oral	Esterase activation and one-step CYP-dependent activation (liver or gut)	1–2 hours	∼5 days	Bleeding (major and minor) and dyspnea in approximately 5% of patients^Citation30
Ticagrelor	R	75%–80%	Oral	None required	1–2 hours	1–2 days	Bleeding, dyspnea in approximately 14% of patients, and ventricular pauses^Citation31
Cangrelor 4 μg/kg/min	R	>90%	Intravenous	None required	Minutes	20 minutes	Bleeding (minor) and dyspnea in approximately 1% of patients^Citation35
Elinogrel 40 mg	R		Oral/intravenous	None required	20 minutes	∼1 day	No increase in bleeding
SCH 530348	R	(>90% to TRAP)	Oral	None required	With LD: hours; without LD: days	Weeks	No increase in bleeding

Abbreviations: ADP, adenosine diphosphate; CYP, cytochrome P450; IRR, irreversible; LD, loading dose; R, reversible; TRAP, thrombin receptor antagonist peptide.

Table 2 Ticagrelor: results of clinical trials

Phase	Clinical trial	Patients	Dosage	Results
Phase 2	DISPERSE^Citation36	200 patients with atherosclerosis	Randomization to ticagrelor (doses of 50, 100, or 200 mg TD, or 400 mg OD) or clopidogrel (75 mg OD), on top of aspirin (75–100 mg OD), for 28 days	Ticagrelor TD produced a more rapid and greater IPA than clopidogrel (90% vs 60%)
	DISPERSE-2^Citation37	990 patients with non-ST-segment elevation ACS	Randomization to ticagrelor (90 or 180 mg TD) or clopidogrel (75 mg OD), on top of aspirin (75 and 100 mg OD), for up to 12 weeks	No difference was observed in the total bleeding rate between 90-mg ticagrelor-treated, 180-mg ticagrelor-treated, and clopidogrel-treated groups (9.8%, 8.0%, and 8.1%, respectively)
	ONSET/OFFSET^Citation38	123 patients with stable CAD	Randomization to ticagrelor (90 mg TD), clopidogrel (75 mg OD), or placebo, on top of aspirin (75–100 mg OD), for 6 weeks	Ticagrelor achieved more rapid and greater platelet inhibition than high-LD clopidogrel >50% IPA (98% vs 31%, P < 0.0001) and >70% IPA (90% vs 16%, P < 0.0001) at 2-h post-LD; this was sustained during the maintenance phase and was faster in offset after drug discontinuation
Phase 3	PLATO^Citation31	18,624 patients with ACS	Randomization to LDs of ticagrelor (180 mg) or clopidogrel (300 mg; with an additional 300 mg clopidogrel at PCI), then ticagrelor (90 mg TD) or clopidogrel (75 mg OD), on top of aspirin (75–100 mg OD), for 6–12 months	Compared with clopidogrel treatment, ticagrelor treatment was found to significantly reduce the rate of death from vascular causes, MI, or stroke (primary end point: 11.7% vs 9.8%, P < 0.001), without an increase in the rate of overall major bleeding

Abbreviations: ACS, acute coronary syndrome; CAD, coronary artery disease; IPA, inhibition of platelet aggregation; LD, loading dose; MI, myocardial infarction; OD, once daily; PCI, percutaneous coronary intervention; TD, twice daily.

CAPRIE Steering CommitteeA randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)Lancet199634813291339

 PubMed Web of Science ®Google Scholar

AntmanEMWiviottSDMurphySAEarly and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel – Thrombolysis In Myocardial Infarction) analysisJ Am Coll Cardiol20085120282033

 PubMed Web of Science ®Google Scholar

WallentinLBeckerRCBudajATicagrelor versus clopidogrel in patients with acute coronary syndromesN Engl J Med200936110451057

 PubMed Web of Science ®Google Scholar

HarringtonRAStoneGWMcNultySPlatelet inhibition with cangrelor in patients undergoing PCIN Engl J Med200936123182329

 PubMed Web of Science ®Google Scholar

HustedSEmanuelssonHHeptinstallSSandsetPMWickensMPetersGPharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirinEur Heart J20062710381047

 PubMed Web of Science ®Google Scholar

CannonCPHustedSHarringtonRASafety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trialJ Am Coll Cardiol2007501844185117980250

 PubMed Web of Science ®Google Scholar

GurbelPABlidenKPButlerKRandomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The ONSET/OFFSET studyCirculation200912025112522

 Web of Science ®Google Scholar