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Abstract

Background:

Antiplatelet therapy is a cornerstone in coronary artery disease management. However, patients with acute coronary syndrome still remain at risk of recurrent cardiovascular events despite the advance of medical therapy.

Objective:

This article provides a review of antiplatelet agents used in cardiovascular diseases and focus on updates in the past 5 years.

Method:

Peer-reviewed clinical trials and relevant treatment guidelines were identified from MEDLINE and Current Content database (from 1966 to April 15, 2013) using search terms aspirin, clopidogrel, prasugrel, ticagrelor, glycoprotein IIb/IIIa inhibitors, antiplatelet agents, coronary artery disease, acute coronary syndrome, pharmacology, pharmacokinetics, and pharmacodynamics. Citations from the available articles were also reviewed for additional references.

Results:

In unstable angina and non-ST-segment elevation myocardial infarction (MI), dual antiplatelet therapy (aspirin and clopidogrel) demonstrated a reduction in death from cardiovascular causes, nonfatal MI, or stroke (relative risk 0.80; 95% confidence interval [CI], 0.72-0.90). In ST-segment elevation MI, dual antiplatelet therapy reduced the rate of occluded infarct-related artery/death or recurrent MI (95% CI, 24%-47%). Newer agents such as prasugrel, when compared to clopidogrel, reduced death from vascular causes, MI, or stroke in patients undergoing percutaneous coronary intervention (PCI; hazard ratio [HR], 0.81; 95% CI 0.73-0.90) but not in those receiving medical management only. When compared to clopidogrel, ticagrelor reduces death from vascular causes, MI, or stroke (HR: 0.84; 95% CI, 0.77-0.92) in patients undergoing PCI or receiving medical management only. Both the agents, however, increase the risk of bleeding in certain patient population.

Conclusions:

In the last 5 years, newer antiplatelet agents, including prasugrel and ticagrelor, have been demonstrated to reduce recurrent cardiovascular events compared to standard therapy and, however, also caused increase bleeding in selected patient populations. Newer agents including shorter acting P2Y12 inhibitor or antiplatelets that target other receptors are being evaluated to improve/maintain therapeutic efficacy yet minimize the risk of bleeding.

Keywords

antiplatelet agents prasugrel ticagrelor acute coronary syndrome

Introduction

Platelets play an important role in normal homeostasis and atherothrombosis by adhering to injured vascular wall, releasing vasoactive and prothrombotic mediators that trigger vasoconstriction and promote coagulation.¹ However, uncontrolled progression of this process can lead to intraluminal thrombus formation, vascular occlusion, and subsequent ischemia or infarction. Coronary artery diseases including stable angina and acute coronary syndromes (ACS) are the leading causes of morbidity and mortality in the United States.² In 2010, approximately 8 million cases of myocardial infarction (MI) were diagnosed.² Thrombotic occlusion of the coronary arteries underlies the pathophysiology of each of these conditions. This occlusion occurs when atherosclerotic plaque ruptures, and platelet aggregation takes place at the site of rupture.¹

Antiplatelet therapy is a cornerstone in coronary artery disease management. They interfere with one or more steps of the process of platelet release and aggregation and reduce the risk of thrombosis. However, the beneficial effect cannot be dissociated from an increased risk of bleeding. Aspirin, thienopyridine P2Y12 receptor antagonists (eg, clopidogrel), and glycoprotein IIb/IIIa inhibitors (eg, abciximab and eptifibatide) are standard therapy, well established to prevent and manage arterial thrombotic events.^3,4 The clinical benefits of dual antiplatelet agent (aspirin + second generation thienopyridine, and clopidogrel) in the management of ACS, especially in patients receiving percutaneous coronary intervention (PCI), are also well established.^5
–7 In unstable angina and non-ST-segment elevation MI (NSTEMI), dual antiplatelet therapy with aspirin and clopidogrel has been demonstrated to reduce death from cardiovascular causes, nonfatal MI, or stroke by a relative risk of 20% (clopidogrel: 9.3%, placebo: 11.4%: relative risk [RR] 0.80; 95% confidence interval [CI], 0.72-0.90; P < .001).^5,6 In STEMI, dual antiplatelet therapy reduces the rate of occluded infarct-related artery on angiography or death or recurrent MI before angiography by 36% (placebo: 21.7%, clopidogrel: 15.0%, (95% CI, 24%-47%; P < .001).⁷ The ClOpidogrel and Metoprolol in Myocardial Infarction Trial study also demonstrated that clopidogrel added to aspirin therapy reduces death, reinfarction, and stroke (9.2% clopidogrel vs 10.1% placebo, P = .002).⁸ In the last 5 years, newer antiplatelet agents have also become available, and even more agents are in the developmental pipeline. This continues to refine the role of antiplatelet agents used in cardiovascular diseases (CVDs). The latest American College of Cardiology Foundation and American Heart Association (AHA) Guidelines on unstable angina and NSTEMI management recommend that dual antiplatelet agents be used for either medical management or patients undergoing PCI.³ For medical management patients, in addition to aspirin, both clopidogrel and ticagrelor are therapeutic options as the second antiplatelet agent. For patients undergoing PCI, in addition to aspirin, clopidogrel, prasugrel, or ticagrelor are all acceptable therapeutic option as the second antiplatelet agent.³ This article provides a review of the pharmacology and clinical efficacy/adverse effects of these agents with focus on update of the newer antiplatelet agents used in this area in the past 5 years.

Method

Peer-reviewed clinical trials, review articles, and relevant treatment guidelines were identified from MEDLINE and Current Content database (both from 1966 to April 15, 2013) using search terms aspirin, clopidogrel, prasugrel, ticagrelor, glycoprotein IIb/IIIa inhibitors, antiplatelet agents, coronary artery disease, acute coronary syndrome, pharmacology, pharmacokinetics, and pharmacodynamics. Citations from available articles were also reviewed for additional references.

Clinical Pharmacology of Antiplatelet Agents

Table 1 summarizes the mechanism of action, pharmacokinetics, and optimal dosing of different antiplatelet agents on the US market.

Table 1.

Pharmacologic Profile of Antiplatelet Agents on the US Market.

	Aspirin	Dipyridamole	Cilostazil	Abciximab	Eptifibatide	Tirofiban	Ticlopidine	Clopidogrel	Prasugrel	Ticagrelor
Mechanism of action	COX-1 inhibitor	Inhibition of cyclic nucleotide phosphodiesterase and blockade of uptake of adenosine	PDE-3 inhibitor	Chimeric human-murine monoclonal antibody Fab fragment GpIIb/IIIa inhibitor	Cyclic heptapeptide GpIIb/IIIa inhibitor	Nonpeptide GpIIb/IIIa inhibitor	Irreversible P2Y12 receptor antagonist (via its active metabolite only)	Irreversible P2Y12 receptor antagonist (via its active metabolite only)	Irreversible P2Y12 receptor antagonist (via its active metabolite only)	Reversible P2Y12 receptor antagonist (both ticagrelor itself and its active metabolite)
Bioavailability	40%-50%	37%-66%	87%-100%	NA	NA	NA	80%-90%	50%	≥79%	36%
Protein binding	50%-80% bound to albumin	99% bound to albumin	95%-98% bound to albumin	NA (bind to platelets)	NA (bind to platelets)	NA (bind to platelets)	98%	Not reported	98% bound to albumin	>99% bound to plasma protein
Metabolism	Hydrolyzed by esterase in liver	Hepatic transformation to monoglucuronide occurs with partial enterohepatic circulation	Metabolized primarily CYP3A4 and, to a lesser extent, CYP2C19	Not metabolized	Deaminated	Not metabolized	Metabolized through N-dealkylation, N-oxidation, and oxidation of the thiophene ring	Metabolized by CYP2C19, CYP3A, CYP2B6, and CYP1A2. Drug is first oxidized to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel	Metabolized by CYP3A4 and CYP2B6, and to a lesser extent by CYP2C9 and CYP2C19. Rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite in 1 single step	Metabolized by CYP3A4 to active metabolite
Half-life	15-20 minutes	10 hours	11 hours	30 minutes	1-2 hours	1-2 hours	12-13 hours	Clopidogrel: 6 hours. Active metabolite: 30 minutes	Prasugrel: 7 hours. Active metabolite: not reported	Ticagrelor: 7 hours. Active metabolite: 9 hours
Dosage (for coronary artery disease unless otherwise specified)	75-325 mg po daily	200 mg extended-release dipyridamole and 25 mg aspirin twice daily (for stroke prevention only)	100 mg po twice daily	0.25 mg/kg bolus IV + 0.125 µg/kg/min	180 µg/kg bolus IV (repeat in 10 minutes for PCI) + 2 µg/kg/min	0.4 µg/kg bolus IV + 0.1 µg/kg/min	500 mg loading po, 250 mg po twice daily	300-600 mg loading po, then 75 mg po once daily	60 mg loading, then 10 mg daily (5 mg if patient is <65 kg)	180 mg po loading, then 90 mg po twice daily
Side effects besides bleeding	Gastrointestinal upsets	Bronchospasm (in patients with history of brochospastic disease)		Thrombocytopenia	Thrombocytopenia	Thrombocytopenia	Neutropenia, thrombocytopenia	Thrombocytopenia		Dyspnea, bradyarrhythmia, headache

Abbreviations: COX-1, cyclooxygenase 1; CYP, cytochrome; Gp, glycoprotein; NA, not applicable; PDE-3, phosphodiesterase 3; po, oral; IV, intravenous; PCI, percutaneous coronary intervention.

Aspirin

Aspirin is the first antiplatelet agent established for its cardiovascular beneficial effect and is the most widely studied and used antiplatelet drug. The best-characterized mechanism of action of aspirin is related to its capacity to permanently inhibit the cyclooxygenase (COX) activity of prostaglandin H-synthase 1 and prostaglandin H-synthase 2 (COX-1 and COX-2, respectively).⁹ The COX isozymes catalyze the conversion of arachidonic acid to prostaglandin H2 (PGH2). The PGH2 is the immediate precursor of thromboxane A2 (TXA2) and prostacyclin (PGI2). The TXA2 induces platelet aggregation and vasoconstriction, whereas PGI2 inhibits platelet aggregation and induces vasodilation. Because TXA2 is largely derived from COX-1 (mostly from platelets), it is highly responsive to aspirin inhibition.⁹

Aspirin is rapidly absorbed in the stomach and upper intestine. Plasma levels peak 30 to 40 minutes after ingestion, and inhibition of platelet function is evident within an hour. In contrast, it can take 3 to 4 hours to reach peak plasma levels after administration of enteric-coated aspirin. Therefore, if a rapid effect is required and only enteric-coated tablets are available, the tablets should be chewed instead of swallowed intact. The oral bioavailability of regular aspirin tablets is 40% to 50%. Aspirin has a half-life of 15 to 20 minutes.¹⁰ Despite rapid clearance of aspirin from the circulation, the platelet inhibitory effects last the life span of the platelet, because aspirin irreversibly inactivates platelet COX-1. Aspirin also acetylates megakaryocyte COX-1, thereby inhibiting thromboxane production in newly released platelets as well as those already in the circulation. The mean life span of human platelets is approximately 10 days, which means that approximately 10% to 12% of the circulating platelets are replaced every day.⁹ Major side effect of aspirin is dose-related bleeding and gastrointestinal distress.

Low-dose aspirin (75-325 mg per day) use has been long established to be associated with a significant reduction in the risk of cardiovascular events.^11,12 The role of low-dose aspirin for the secondary prevention (in individuals with coronary artery disease, peripheral vascular disease, or cerebrovascular disease) of cardiovascular events is well established, while its use in primary prevention is more controversial.^13,14 The decision of use of aspirin as primary prevention therapy is dependent on a balance of an individual’s risk of cardiovascular events and adverse treatment effects, such as bleeding.¹⁵ Odd ratios for bleeding, in case–control studies of low-dose aspirin, range between 1.3 and 3.2.¹⁶ The US Food and Drug Administration has not been adequately persuaded that there is sufficient evidence of a net benefit for aspirin use in primary prevention in all patients.¹⁷ The AHA, however, recommends low-dose aspirin in individuals with an estimated ≥10% risk of a cardiovascular event over a 10-year period.¹⁸ Similarly, the US Preventive Services Taskforce recommends aspirin in men aged 45 to 79 years in whom the benefit of a reduction in MI outweighs the harm of an increased risk of gastrointestinal bleeding, and in women aged 55 to 79 years in whom the benefit of a reduction in the risk of ischemic stroke outweighs the same risk of harm.¹⁹ For older adults, they recommend a 12% risk of a cardiovascular event over 10 years as the cutoff when the benefit exceeds the risk in those aged 70 to 79 years. For people with diabetes, the American Diabetes Association acknowledges the lack of a clear role for aspirin in primary prevention and currently recommends its use in patients with diabetes who have a 10-year CVD risk of over 10%.^20,21

Glycoprotein IIb/IIIa Inhibitors

Glycoprotein (Gp) IIb/IIIa inhibitors prevent platelet aggregation by blocking fibrinogen binding to the GpIIb/IIIa receptors on the platelet, thus preventing linking of platelets, the final step of platelet aggregation. Three parenteral glycoprotein IIb/IIIa inhibitors are available on the US market. Abciximab is a humanized version of a Fab fragment of a murine antibody directed against GpIIb-IIIa. Platelet aggregation is nearly completely abolished with >80% receptor blockade.²² After intravenous bolus administration, pharmacokinetic data indicate that free plasma abciximab concentrations decrease rapidly (initial half-life of about 30 minutes), reflecting the rapid binding of the antibody to GpIIb-IIIa.²² Peak effects on receptor blockade, platelet aggregation, and bleeding time were observed at 2 hours. This was followed by gradual recovery of platelet function, with bleeding times returning to baseline by 12 hours.^22,23 Thrombocytopenia occurs in 1% to 2% of the patients treated with abciximab. The risk of thrombocytopenia appears to be increased with abciximab readministration. Typically, the decrease in platelet count occurs within 24 hours of initiation of treatment but may begin to fall as early as 2 hours after the treatment starts.⁹ Abciximab has been demonstrated to decrease the risk of events compared with placebo in high-risk patients with NSTEMI scheduled for PCI after treatment with clopidogrel. In a meta-analysis of studies assessing patients presenting for primary PCI and stenting of STEMI (n = 1101), death or reinfarction was also reduced in patients receiving abciximab versus placebo.²⁴

Tirofiban is a nonpeptide tyrosine derivative that selectively binds to GpIIb-IIIa. The plasma half-life of tirofiban is 1.5 to 2 hours, and both renal and biliary excretion contribute to tirofiban clearance with unchanged tirofiban found in urine and feces.²⁵ Dose adjustment is required in patients with renal insufficiency but not in patients with hepatic disease. Severe, but reversible, thrombocytopenia has been reported in a small percentage of patients treated with tirofiban.²⁶ In a meta-analysis (n = 20 006), tirofiban used in patients with unstable angina and NSTEMI scheduled for PCI was significantly more effective than placebo at reducing the risk of mortality or the composite of death and MI at 30 days.²⁷

Eptifibatide is a synthetic disulfide-linked cyclic heptapeptide. It is formulated after the KGD sequence found in the snake venom disintegrin obtained from Sistrurus miliarius barbouri (barbourin) and has high specificity for GpIIb-IIIa.⁹ Because the drug is cleared by the kidneys, patients with renal impairment exhibit prolonged inhibition of platelet function after receiving eptifibatide and required dosage adjustment.²⁸ Eptifibatide treatment has also been associated with thrombocytopenia, and an immunologic mechanism has been identified in some patients.²⁶ In one study in patients with unstable angina and NSTEMI undergoing PCI, eptifibatide did not show significant benefit when compared with placebo.²⁹ However, in a subsequent trial investigating higher doses, a significant reduction in the risk of death, MI, urgent coronary revascularization, and bail-out use of GPIIb/IIIa inhibitors was demonstrated versus placebo.³⁰ More recently, it has been shown that early administration of eptifibatide presented no advantage over postangiographic administration.³¹

Dipyridamole

Dipyridamole is a pyrimidopyrimidine derivative with vasodilator and antiplatelet properties. The mechanism of action of dipyridamole as an antiplatelet agent is controversial. Both inhibition of cyclic nucleotide phosphodiesterase (the enzyme that degrades cyclic adenosine monophosphate [cAMP]) and blockade of the uptake of adenosine (which binds to A2 receptors, stimulates platelet adenylyl cyclase, and increases cAMP) have been suggested.⁹ The cAMP is an inhibitor for platelet aggregation. The absorption of dipyridamole is variable and results in low-systemic bioavailability of the drug. A modified release formulation of dipyridamole with improved bioavailability has been developed in a combination pill with low-dose aspirin.³² Dipyridamole is highly protein bound to albumin, eliminated primarily by biliary excretion as a glucuronide conjugate, and is subject to enterohepatic recirculation. Half-life of dipyridamole is 10 hours.⁹ The use of dipyridamole for primary or secondary prevention of coronary artery disease is not well established.

Cilostazil

Cilostazol is a 2-oxoquinolone derivative that is reported to have vasodilatory and antiplatelet properties, via phosphodiesterase 3 inhibitory effect, as well as antiproliferative properties reducing smooth muscle cell proliferation and neointimal hyperplasia after endothelial injury. Cilostazol is contraindicated in patients with heart failure because of the potential to trigger ventricular tachycardia. There is substantial variability in the absorption of orally administered cilostazol. Cilostazol is highly albumin bound and is extensively metabolized by cytochrome P450 (CYP450) enzymes with excretion of metabolites in the urine. It has a half-life of 11 hours.⁹ Cilostazil is indicated for symptomatic peripheral arterial disease, but its role in primary or secondary prevention of coronary artery disease is not well established.

P2Y12 receptor antagonists

Ticlopidine, clopidogrel, and prasugrel represent 3 generations of oral thienopyridines that inhibit adenosine diphosphate (ADP)-induced platelet aggregation. The use of first-generation agent ticlopidine was limited by its bone marrow toxicity (neutropenia) and has largely been replaced by clopidogrel that has become established as standard therapy across the spectrum of patients with coronary artery disease and in those undergoing PCI. However, clopidogrel also has limitations, including variable absorption; variable antiplatelet effects related, at least in part, to common polymorphisms in the genes that regulate the metabolic activation of clopidogrel; and a delayed onset and offset of action. Prasugrel, a more recently available, third-generation thienopyridine, has a more rapid onset of action, is more potent than clopidogrel, and produces more consistent platelet inhibition. All 3 thienopyridines are prodrugs that must undergo metabolic activation through the hepatic CYP450 system to generate the active metabolites that exert their pharmacologic action.

Ticlopidine

Up to 90% of a single oral dose of ticlopidine is rapidly absorbed.¹⁸ Plasma concentrations peak 1 to 3 hours after a single-oral dose of 250 mg. More than 98% of the absorbed ticlopidine is reversibly bound to plasma proteins, primarily albumin. Ticlopidine is metabolized rapidly and extensively. A total of 13 metabolites have been identified in humans.¹⁸ The apparent half-life of ticlopidine is 24 to 36 hours after a single oral dose and up to 96 hours after 14 days of repeated dosing. The standard dosing regimen of ticlopidine is 250 mg twice a day.³³

Clopidogrel

Clopidogrel is also rapidly absorbed and metabolized through a 2-step process to generate an active metabolite that irreversibly binds to the platelet P2Y12 receptor.³⁴ On repeated daily dosing of 50 to 100 mg of clopidogrel in healthy volunteers, ADP-induced platelet aggregation was inhibited from the second day of treatment (25%-30% inhibition) and reached a steady state (50%-60% inhibition) after 4 to 7 days. Such a level of inhibition was comparable to that achieved with ticlopidine (500 mg/d), although the antiplatelet effects of the latter were more delayed than that of clopidogrel.³⁴ Loading dose (eg, 300 mg) of clopidogrel results in more rapid platelet inhibition (6-12 hours) than that achieved with the 75 mg dose.³⁵ After loading with 600 mg of clopidogrel, the full antiplatelet effect of the drug was achieved after 2 to 4 hours.³⁶ Moreover, a loading dose of 600 mg resulted in higher plasma concentrations of the active metabolite and the inactive carboxyl metabolite compared with a loading dose of 300 mg.³⁶ Inhibition of ADP-induced platelet aggregation was also significantly greater with a 600 mg loading dose of clopidogrel compared with a 300 mg loading dose.³⁷ The incremental antiplatelet effect of 900 mg over 600 mg of clopidogrel appears marginal.^37,38 Platelet function returns to baseline 7 to 10 days after the last dose of clopidogrel. This also justifies a once-daily regimen for aspirin and clopidogrel in patients with normal rates of platelet turnover despite short half-life of both the drugs in the circulation.

Prasugrel

Prasugrel is rapidly absorbed after oral administration and converted into its active metabolite, which reaches peak concentrations within 30 minutes of dosing. The active metabolite has a half-life of approximately 4 hours, and renal excretion is the major route for elimination.³⁹ Initial pharmacological studies with prasugrel in healthy individuals³⁹ and in patients with stable coronary artery disease³² showed that prasugrel has a more rapid onset of action than clopidogrel and achieves more consistent and complete inhibition of ADP-induced platelet aggregation.^40,41 The more rapid onset of action of prasugrel may in part reflect the hepatic conversion to its active metabolite by CYP450 enzymes in a single step, which contrasts with that of clopidogrel that undergoes a 2-step hepatic conversion process.⁴² Unlike clopidogrel, evidence showed that polymorphisms in CYP2C19 or the concomitant use of proton-pump inhibitors did not interfere with the metabolism of prasugrel.^43,44 Clinical studies on the use of prasugrel in patients with coronary artery disease will be discussed in greater depth in the clinical trial section.

Ticagrelor

Ticagrelor is the first member of a new class of antiplatelet agent, the cyclopentyl-triazolopyrimidines.⁴⁵ Ticagrelor is an orally active, selective antagonist of the P2Y12 receptor, inhibiting ADP-mediated platelet response. Ticagrelor demonstrates noncompetitive antagonistic activity for ADP-induced platelet aggregation.⁴⁶ Unlike clopidogrel and prasugrel, ticagrelor demonstrates platelet inhibitory activity without the need for metabolic activation. In addition, its active metabolite (AR-C124910XX) is also active and demonstrates P2Y12 receptor antagonism activity equipotent to ticagrelor.^47,48

Ticagrelor was rapidly absorbed with a maximum plasma concentration occurring at 1.5 hours. The major active metabolite, AR-C124910XX, is formed by O-deethylation (via CYP3A4) and represents approximately 40% of the parent concentration. The plasma elimination half-life of ticagrelor was found to be 7.2 hours.⁴⁹ Clinical trials evaluating the use of ticagrelor in patients with coronary artery disease will be discussed subsequently.

Clinical Trials Updates: Updates From the Last 5 years

Prasugrel

The majority of the clinical outcomes data for prasugrel comes from the phase III Trial to Access Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) trial. In this study, 13 608 patients with ACS with planned PCI (10 074 patients with moderate to high-risk unstable angina and NSTEMI and 3534 patients with STEMI) were randomized to receive either clopidogrel 300 mg loading dose followed by 75 mg daily or prasugrel 60 mg loading dose followed by 10 mg daily.⁵⁰ Patients were treated for a median of 14.5 months. The primary end point was the composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. Patients randomized to prasugrel had fewer primary end point events compared with clopidogrel (9.9% vs 12.1%; hazard ratio [HR], 0.81; 95% CI, 0.73 to 0.90; P < .001). The reduction in clinical ischemic events was also notable for a reduction in MI (7.4% vs 9.7%, P < .001) and urgent target vessel revascularization (2.5% vs 3.7%; P < .001). The major safety end point of noncoronary artery bypass graft (CABG)-related TIMI major bleeding was significantly higher with prasugrel (2.4% vs 1.8%; HR, 1.32; 95% CI, 1.03-1.68; P < .03). There was also significant increase in non-CABG-related TIMI major or minor bleeding (5.0% vs 3.8%; HR, 1.31; 95% CI, 1.11-1.56; P < .002) and bleeding requiring transfusion (4.0% vs 3.0%; HR, 1.34; 95% CI, 1.11-1.63; P < .001). Among non-CABG-related bleeding, the excess was predominantly spontaneous bleeding (1.6% vs 1.1%; HR, 1.51; 95% CI, 1.09-2.08; P < .01). Intracranial bleeding was not significantly increased (0.3% of both treatment arms). Patients with known history of stroke or transient ischemic attacks (n = 518) before enrollment in TRITON-TIMI 38 trial had a higher rate of primary efficacy events (19.1% vs 14.4%; HR, 1.37; P < .15) driven by an increase in stroke, which differed significantly from the nonstroke cohort (P for interaction <.02). They also have significantly higher rate of bleeding, including more intracranial hemorrhage (23.0% vs 16.0%; HR, 1.54; P < .04). In patients >75 years of age (n = 1809), a smaller relative reduction in primary efficacy events (17.2% vs 18.3%; HR, 0.94; P = .60) and an absolute TIMI major bleeding rates (4.2% vs 3.4%; HR, 1.36; P = .24) were observed. This resulted in a neutral net outcome (21.7% vs 21.5%; HR, 0.99; P = .92). Similar bleeding concern was also observed in the elderly patients. In patients >75 years of age, 9 spontaneous fatal hemorrhages were observed with prasugrel and 0 with clopidogrel. In patients <75 years of age, 5 fatal spontaneous hemorrhages were observed with prasugrel and 4 with clopidogrel. Patients with low body weight (<60 kg; n = 668) also had higher rates of bleeding (6.0% vs 3.5%; HR, 1.90; P < .09).⁵⁰

A subanalysis of the TRITON-TIMI 38 trial was also performed in 12 844 patients who received at least 1 coronary stent (5743 drug eluting stent, 6461 bare metal stent). Prasugrel compared to clopidogrel reduced the incidence of primary end points in this stent cohort (9.7% vs 11.9%, P = .0001). Definite or probable stent thrombosis was reduced by 52% (1.1% vs 2.4%; HR, 0.48; 95% CI, 0.36-0.64; P < .001), and definite stent thrombosis demonstrated by angiogram or autopsy was reduced by 58% (0.9% vs 2.0%; HR, 0.42; 95% CI, 0.31-0.59; P < .001) in patients who received prasugrel. These findings were similar whether patients received bare metal stents or drug-eluting stents.⁵¹ The reduction in stent thrombosis was noted within 30 days after randomization (0.64% vs 1.56%; HR, 0.41; 95% CI, 0.29-0.59; P < .0001) and after 30 days (0.49% vs 0.82%; HR, 0.60; 95% CI, 0.37-0.97; P < .03).

Additional subanalyses of the TRITON-TIMI 38 trial also suggest that the magnitude of effect of prasugrel was enhanced in 3146 patients with history of diabetes mellitus (primary end point occurred in 12.2% with prasugrel vs 17.0% with clopidogrel; HR 0.70 (95% CI 0.58-0.85; P < .001)⁵² and in those presenting with STEMI (n = 3534) treated with primary or delayed PCI (primary end point at 15 months of 10.0% with prasugrel vs 12.4% with clopidogrel; HR 0.79 (95% CI 0.65-0.97); P = .0221⁵³ without any increase in major bleeding. Further, no significant association existed between tested CYP genotype and the risk of the composite of cardiovascular death, MI, or stroke.⁵⁴

The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndrome (TRILOGY-ACS) study examined the use of prasugrel versus clopidogrel in 7243 patients <75 years of age and 2083 patients ≥75 years, with unstable angina or NSTEMI who were selected to receive medical management only.⁵⁵ Patients were randomized to prasugrel 10 mg daily (5 mg for patients ≥75 years) or clopidogrel 75 mg daily, in addition to aspirin therapy. The primary end point of the study was death from cardiovascular causes, MI, or stroke. Among the primary cohort of patients aged <75 years and at a median followup of 17 months, there was no significant between-group difference in the rate of the primary end point, which occurred in 13.9% of the patients receiving prasugrel compared with 16.0% of the patients receiving clopidogrel (HR 0.91 [95% CI 0.79-1.05]; P = .21). Similar results were observed in the overall population (18.7% vs 20.3%; HR 0.96 [95% CI 0.86-1.07]; P = .45). Rates of severe and intracranial bleeding were similar in both the groups among all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group in patients <75 years (1.8% vs 1.3%, P = .045).

Ticagrelor

The Phase III clinical trial that demonstrates the efficacy and tolerability of the use of ticagrelor in ACS is the ticagrelor versus clopidogrel in Patients with Acute Coronary Syndrome (PLATO) study.⁵⁶ This is a multicenter, double-blind, randomized trial that enrolled 18 624 patients admitted to the hospital within 24 hours of an ACS event. Patients were randomized to receive oral ticagrelor 180 mg loading dose and 90 mg twice daily thereafter or oral clopidogrel 300 to 600 mg loading dose and 75 mg daily thereafter. The primary end point of the study is a composite of death from vascular causes, MI, or stroke. After 12 months followup, primary end point events occurred in 9.8% of the patients in the ticagrelor group and 11.7% of the patients in the clopidogrel group (HR: 0.84; 95% CI, 0.77-0.92, P < .001). Predefined secondary end points also showed significant differences in rates of other composite end points (death from any cause, MI, or stroke: ticagrelor 10.2% vs clopidogrel 12.3%, P < .001; death from vascular causes, MI, stroke, recurrent ischemia, transient ischemic attack, or other thrombotic event: ticagrelor 14.6% vs clopidogrel 16.7%, P < .001), MI alone (ticagrelor 5.8% vs clopidogrel 6.9%, P = .005), and death from vascular causes (ticagrelor 4% vs clopidogrel 5.1%, P = .001). No significant difference in the rates of major bleeding was found between the ticagrelor and the clopidogrel groups (11.6% and 11.2%, P = .43), but ticagrelor was associated with a higher rate of non-CABG-related major bleeding (4.5% vs 3.8%, P = .03), including more instances of fatal intracranial bleeding (0.1% vs 0.01%, P = .02) and fewer of fatal bleeding of other types (0.1% vs 0.3%, P = .03). This study demonstrates that in patient with ACS, treatment with ticagrelor as compared with clopidogrel significantly reduces the rate of death from vascular causes, MI, or stroke without an increase in rate of overall major bleeding but with an increase in rate of nonprocedure-related major bleeding. Ticagrelor is also reported to cause dyspnea in 13.8% of the patients. This is significantly higher in incidence than clopidogrel (7.8%, P < .001).⁵⁶ Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment.⁵⁷ In a substudy,199 patients from PLATO (101 ticagrelor and 98 clopidogrel) underwent pulmonary function testing irrespective to whether they reported dyspnea.⁵⁸ There was no significant difference between treatment groups for forced expiratory volume in the first second of expiration (ticagrelor 2.81 L and clopidogrel 2.70 L). There was no indication of an adverse effect on pulmonary function assessed after 1 month or after at least 6 months of chronic treatment.

Ticagrelor has also been shown to increase the occurrence of Holter-detected bradyarrhythmias (including ventricular pauses).⁵⁹ In a Holter substudy, a total of 2908 patients were included in the continuous electrographic assessment, of whom 2866 (98.5%) had week 1 recordings, 1991 (68.4%) had 1-month recordings, and 1949 (67.0%) had both. During the first week after randomization, ventricular pauses ≥3 seconds occurred more frequently in patients receiving ticagrelor than clopidogrel (5.8% vs 3.6%; RR: 1.61; P = .006). At 1 month, pauses ≥3 seconds occurred overall less frequently and were similar between treatments (2.1% vs 1.7%). There were no differences between ticagrelor and clopidogrel in the incidence of clinically reported bradycardic adverse events. Ticagrelor is structurally similar to adenosine⁵⁷ and therefore may partially explain some of its side effects similar to that of adenosine such as dyspnea and bradyarrhythmia.

Several subanalyses were performed with PLATO. One subanalysis was performed in patients who underwent planned invasive strategy (PCI or CABG) for management of their ACS.⁶⁰ In all, 6732 patients undergoing invasive strategy were assigned to ticagrelor and 6676 patients were assigned to clopidogrel. The primary composite end point occurred in fewer patients in the ticagrelor group than in the clopidogrel group (9.0% vs 10.7%, HR 0.84, 95% CI 0.75-0.94; P = .0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (11.6% vs 11.5%, HR 0.99, 95% CI 0.89-1.10; P = .8803) or severe bleeding (3.2% vs 2.9%, HR 0.91, 95% CI 0.74-1.12; P = .3785).

Another PLATO substudy was also performed looking at patients with ACS who were managed by medical treatment only.⁶¹ In all, 3143 patients were managed noninvasively. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% vs 14.3%; HR 0.85, 95% CI 0.73-1.00; P = .04). Overall mortality was also lower (6.1% vs 8.2%; HR 0.75, 95% CI 0.61-0.93; P = .01). The incidence of total major bleeding (11.9% vs 10.3%; HR 1.17, 95% CI 0.98-1.39; P = .08) and non-CABG-related major bleeding (4.0% vs 3.1%; HR 1.30, 0.95-1.77; P = .10) was not significantly different between ticagrelor and clopidogrel.

The subpopulation in the PLATO trial that underwent CABG was also examined in a separate subanalysis.⁶² The protocol recommended ticagrelor to be withheld for 24 to 72 hours and clopidogrel for 5 days preoperatively. In all, 1261 patients underwent CABG and were receiving study drug treatment <7 days before surgery. The relative reduction in primary composite end point was observed at 12 months (10.6% with ticagrelor vs 13.1% with clopidogrel; HR: 0.84; 95% CI: 0.60-1.16; P = .29). There was no significant difference in CABG-related major bleeding between the randomized treatments.

Patients in PLATO with STEMI (n = 7544) were also subanalysed.⁶³ There is no differences in primary end point between the 2 treatment groups (clopidogrel 10.8% vs ticagrelor 9.4%; HR, 0.87; 95% CI, 0.75-1.01; P = .07). There is no difference between ticagrelor and clopidogrel in terms of major bleeding in this subgroup of patients (HR, 0.98; P = .76).

The efficacy of ticagrelor in relation to renal function has also been analyzed using the PLATO patient population.⁶⁴ Serum creatinine levels were available in 15 202 (81.9%) of the patients enrolled in the PLATO study. Creatinine clearance was estimated by Cockcroft Gault equation. In patients with chronic kidney disease (creatinine clearance <60 mL/min; n = 3237), ticagrelor versus clopidogrel significantly reduced the primary end point from 22.0% to 17.3% (HR, 0.77; 95% CI, 0.65-0.90, P < .05) with an absolute risk reduction greater than that of patients with normal renal function (n = 11 965): 7.9% versus 8.9% (HR: 0.90; 95% CI, 0.79-1.02, P > .05). Major bleeding rates, fatal bleedings, and noncoronary bypass-related major bleedings were not significantly different between the 2 randomized groups (15.1% vs 14.3%; HR 1.07; 95% CI, 0.88-1.30; 0.34% vs 0.77%; HR 0.48, 95% CI 0.15-1.54; and 8.5% vs 7.3%; HR 1.28; 95% CI, 0.97-1.68). Therefore, in patients with ACS and chronic kidney disease, ticagrelor compared to clopidogrel significantly reduces ischemic end points and mortality without significantly increased risk of major bleeding.

The efficacy of ticagrelor in patients with diabetes has also been analyzed using the PLATO patient population.⁶⁵ In patients with diabetes (n = 4662), ticagrelor reduced the primary end point, all-cause mortality, and stent thrombosis in patients with hemoglobin A_1c (HbA_1c) above the median (defined as HbA_1c of 6%; HR: 0.80, 95% CI: 0.70-0.91; HR: 0.78, 95% CI: 0.65-0.93; and HR: 0.62, 95% CI: 0.39-1.00, respectively, P < .05 for all) with similar bleeding rates (HR: 0.98, 95% CI: 0.86-1.12).

Discussions and Future Perspectives

Efforts to reduce the incidence of recurrent events in patients with ACS have resulted in a rapid evolution with respect to antiplatelet therapy. The availability of newer ADP P2Y12 receptor inhibitors that are more potent than clopidogrel, such as prasugrel and ticagrelor, has increased the therapeutic options for platelet inhibition after ACS. However, the improvement in efficacy often comes with increase in the incidence of bleeding, especially in the high-risk patient populations. Several other therapeutic strategies are currently under investigation for the treatment of ACS. The goal is to maintain/improve efficacy yet reduce the risk of bleeding.

Cangrelor

Cangrelor is another cyclopentyl-triazolopyrimidine, which reversibly inhibits the P2Y12 receptor and does not require metabolic conversion for activity.⁶⁵ It is given intravenously and has a short average half-life of 2.6 minutes.⁶⁶ The majority of patients (∼70%) recovered more than 60% of their baseline aggregation response by 1 hour after infusion.⁶⁷ The potential advantage of a short-acting P2Y12 inhibitor is that there will be less delay should patients require bypass surgery. Cangrelor was studied in 2 large phase III trials with PCI (CHAMPION-PLATFORM and CHAPMION-PHEONIX) and demonstrated significant reduction in rate of ischemic event, including stent thrombosis.^68,69 Compared with placebo, major bleeding appeared to be more frequent due to increased groin hematomas.⁶⁸ Similar to ticagrelor, cangrelor is associated with higher frequencies of dyspnea.^68,69 The fast onset and offset of action of cangrelor may make it a desirable therapeutic option for patients with ACS undergoing PCI before committing patients to one of the longer acting oral antiplatelet agents for chronic therapy.

Protease Activated Receptor 1 Inhibitors

Thrombin is one of the most potent platelet activators, and protease activated receptor 1 (PAR-1) is the principal thrombin receptor on human platelets. However, unlike ADP and TXA2 pathways, which are crucial in both physiological hemostasis and pathological thrombosis, preclinical evidence suggests PAR-1-mediated platelet activation does not appear to be involved in protective hemostasis. It has been hypothesized that combining a PAR-1 inhibitor with existing treatment may increase platelet inhibition without further increasing the risk of bleeding.⁷⁰ Currently, 2 PAR-1 inhibitors are under clinical investigation, vorapaxar and atopaxar, and vorapaxar has entered Phase III clinical trials. Vorapaxar is a high affinity, oral antagonist of the PAR-1 receptor.⁷¹ In a recent large clinical trial, Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome patients (n = 13 000) receiving vorapaxar did not experience improvement in the primary efficacy end point (a composite of death from cardiovascular causes, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) versus placebo. Furthermore, vorapaxar significantly increased the incidence of moderate and severe bleeding as well as intracranial haemorrhage.⁷² This is consistent with a large-scale secondary prevention trial (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events [TRA-2P/TIMI 50]), where an increase in intracranial hemorrhage was detected in patients with a history of stroke. This trend continued in patients in the TRA-2P/TIMI 50 trial, where the data and safety monitoring board recommended the discontinuation of vorapaxar in patients with a history of stroke on the basis of an excess of intracranial hemorrhage. The overall trial, however, showed that in 26 449 patients with a history of MI, ischemic stroke, or peripheral arterial disease (PAD), vorapaxar 2.5 mg daily significantly reduced the primary efficacy end point, a composite of death from cardiovascular causes, MI, or stroke compared with placebo (9.3% vs 10.5%, respectively; HR 0.87 [95% CI 0.80, 0.94]; P < .001).⁷³ The role of PAR-1 inhibitor in management of coronary artery disease needs to be further defined.

Conclusions

Antiplatelet therapy, including aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors, is a cornerstone in coronary artery disease management. However, with the advances made in the area of antiplatelet therapy in the last few years, patients with ACS still remain at risk of recurrent cardiovascular events. In the last 5 years, newer antiplatelet agents including prasugrel and ticagrelor have become available. Each has demonstrated reduced recurrent cardiovascular events compared to standard therapy and, however, also caused increased bleeding in selected patient populations. Newer agents including shorter acting P2Y12 inhibitors, such as cangrelor or antiplatelets that target other receptors, are being evaluated to attempt to improve/maintain therapeutic efficacy yet minimize the risk of bleeding.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Updates in Antiplatelet Agents Used in Cardiovascular Diseases

Abstract

Background:

Objective:

Method:

Results:

Conclusions:

Keywords

Introduction

Method

Clinical Pharmacology of Antiplatelet Agents

Aspirin

Glycoprotein IIb/IIIa Inhibitors

Dipyridamole

Cilostazil

P2Y12 receptor antagonists

Ticlopidine

Clopidogrel

Prasugrel

Ticagrelor

Clinical Trials Updates: Updates From the Last 5 years

Prasugrel

Ticagrelor

Discussions and Future Perspectives

Cangrelor

Protease Activated Receptor 1 Inhibitors

Conclusions

Footnotes

Declaration of Conflicting Interests

Funding

References