New developments in P2Y12 antagonists

Adenosine diphosphate, an important platelet agonist in vivo, has two types of receptors in the platelet plasma membrane: P2Y₁ and P2Y₁₂. The antiplatelet drugs ticlopidine (Ticlid, Roche Laboratories) and clopidogrel (Plavix, Sanofi Aventis/Bristol-Myers Squibb) are thienopyridines that are metabolized through cytochrome P450 in the liver. Thienopyridine metabolites, not the parent molecules, irreversibly antagonize the P2Y₁₂ receptor. Ticlopidine has been largely replaced in clinical practice by clopidogrel because of the better side-effect profile of clopidogrel

The antithrombotic benefit of adding clopidogrel to aspirin therapy has been demonstrated by large multicenter, randomized, controlled trials in patients with acute coronary syndrome, unstable angina, non-ST elevation myocardial infarction, and ST-elevation myocardial infarction, and in patients undergoing percutaneous coronary intervention (PCI).

However, in patients with stable cardiovascular disease or asymptomatic patients with multiple cardiovascular risk factors, the CHARISMA trial demonstrated that the combination of clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. Furthermore, the risk of moderate-to-severe bleeding was increased. In a retrospective analysis of the CHARISMA trial, dual antiplatelet therapy with clopidogrel and aspirin in the primary prevention subgroup of patients was associated with an increase in cardiovascular death. The cause of this apparent harm has not been elucidated.

Alan D. Michelson

Monitoring of clopidogrel by platelet function assays reveals interpatient response variability. Furthermore, there is evidence that a poor response in such in vitro assays (ie, clopidogrel hyporesponsiveness or “resistance”) predicts a poor clinical response to clopidogrel. Thus, clopidogrel hyporesponsiveness, as defined by ADP-induced turbidometric platelet aggregation, ADP-induced platelet aggregation measured by impedance (eg, Multiplate, Dynabyte), VerifyNow P2Y12 Assay (Accumetrics; a point-of-care device that measures ADP-induced platelet aggregation), phosphorylation of vasodilator-stimulated phosphoprotein (VASP), and the thromboelastogram (TEG) PlateletMapping System (Haemoscope), has been reported to be associated with post-PCI major adverse clinical events.

Four factors may be of particular importance with regard to clopidogrel hyporesponsiveness or “resistance.” First, if a patient is noncompliant with taking clopidogrel or only taking it intermittently, the patient will appear by platelet function testing to be hyporesponsive or “resistant” to clopidogrel. Second, drugs that are, like clopidogrel, metabolized through cytochrome P450 in the liver may reduce clopidogrel’s effectiveness. One important example of this phenomenon is proton pump inhibitors, although this may be specific to omeprazole. In contrast, cigarette smoking, presumably by induction of CYP1A2, increases clopidogrel’s effectiveness.

Third, a very common reduced-function CYP2C19 allele results in significantly lower levels of the active metabolite of clopidogrel, with resultant diminished platelet inhibition and a higher rate of major adverse cardiovascular events. In contrast, prasugrel, because of its different hepatic metabolism, is unaffected by the reduced-function CYP2C19 allele; ticagrelor and cangrelor are unaffected because they do not require metabolism.

Fourth, as determined by a number of different platelet function assays, there is evidence in both normal patients and in patients where pre-clopidogrel response to ADP predicts post-clopidogrel response to ADP. These data demonstrate that the variability is in part in the platelet response to ADP rather than solely in the platelet response to clopidogrel.

Continuing interrelated challenges with regard to clopidogrel treatment include 1) the above-discussed phenomenon of clopidogrel hyporesponsiveness or “resistance,” 2) the relatively slow onset of action of clopidogrel, and 3) the still significant incidence of stent thrombosis in patients treated with clopidogrel and aspirin. This has led to the development of novel P2Y₁₂ antagonists.

Prasugrel

Prasugrel (Efient, Eli Lilly & Co./Daiichi Sankyo) is an orally-administered thienopyridine prodrug that, like clopidogrel, is metabolized via cytochrome P450 in the liver. The active metabolite of prasugrel irreversibly inhibits the platelet P2Y₁₂ receptor to a similar extent to the active metabolite of clopidogrel. However, there is much more efficient in vivo generation of the active metabolite of prasugrel than of the active metabolite of clopidogrel. As a result, a prasugrel 60-mg loading dose results in a much more rapid, potent, and consistent inhibition of platelet function than both the standard clopidogrel loading dose of 300 mg and the increasingly used clopidogrel loading dose of 600 mg. Furthermore, a maintenance dose of prasugrel 10 mg daily results in a more potent and consistent inhibition of platelet function than both the standard clopidogrel maintenance dose of 75 mg daily and clopidogrel 150 mg daily.

TRITON-TIMI 38, a 13,608-patient phase-3 trial, demonstrated that in patients with acute coronary syndrome with scheduled PCI, prasugrel (60-mg loading dose and a 10-mg daily maintenance dose), as compared with approved doses of clopidogrel (300-mg loading dose and a 75-mg daily maintenance dose), was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding.

A post-hoc subgroup exploratory analysis of the TRITON-TIMI 38 data identified three subgroups of interest that had less clinical efficacy and greater absolute levels of bleeding than the overall cohort, resulting in less net clinical benefit or in clinical harm. These subgroups were patients with a history of stroke or transient ischemic attack, age older than 75 years, and body weight < 60 kg.

The TRITON-TIMI 38 platelet substudy showed that prasugrel resulted in greater inhibition of ADP-mediated platelet function in patients with acute coronary syndrome than clopidogrel, supporting the hypothesis that greater platelet inhibition leads to a lower incidence of ischemic events and more bleeding both early and late following PCI. In a prespecified TRITON-TIMI 38 study of 3,534 patients with ST-elevation myocardial infarction undergoing PCI, prasugrel was more effective than clopidogrel for prevention of ischemic events, without an apparent excess in bleeding.

Largely based on the TRITON-TIMI 38 trial, prasugrel is now approved in Europe for the prevention of atherothrombotic events in patients with acute coronary syndrome undergoing PCI, and FDA approval is pending. Additional phase-3 clinical trials of prasugrel are in progress.

Ticagrelor

Ticagrelor (AZD6140, AstraZeneca) is an investigational P2Y₁₂ antagonist. Unlike ticlopidine, clopidogrel, and prasugrel, ticagrelor is 1) not a thienopyridine, but a cyclo-pentyl-triazolo-pyrimidine, 2) a direct P2Y₁₂ antagonist (ie, no metabolism of a prodrug is required), and 3) a reversible P2Y₁₂ antagonist.

Like prasugrel, ticagrelor 1) results in a more rapid onset of action and greater degree of platelet inhibition than clopidogrel, 2) maintenance therapy results in more potent inhibition of platelet function than the standard clopidogrel maintenance dose of 75 mg daily, 3) showed no significant increase in major bleeding compared with clopidogrel in phase-2 studies. In these phase-2 studies, dyspnea was greater, in an apparently dose-dependent manner, in patients on ticagrelor compared with patients assigned clopidogrel. Ticagrelor is given orally twice a day. Results of PLATO, a phase-3 trial of ticagrelor in patients with acute coronary syndrome, will be presented at the European Society of Cardiology annual meeting in August.

Cangrelor

Cangrelor (The Medicines Company) is an investigational, direct-acting, reversible P2Y₁₂ antagonist. Unlike the above-described, orally-administered P2Y₁₂ antagonists, cangrelor is administered intravenously. Like prasugrel and ticagrelor, cangrelor results in a more rapid onset of action and greater degree of platelet inhibition than clopidogrel, and showed no significant increase in major bleeding compared with clopidogrel in phase-2 studies. Cangrelor underwent two phase-3 trials, which were stopped early for lack of efficacy. Cangrelor is still being studied as a bridge for patients on clopidogrel who need to go off the drug to undergo surgery.

Elinogrel

Elinogrel (PRT060128, Novartis) is an investigational, direct-acting, reversible P2Y₁₂ antagonist with a novel structure. Elinogrel, which can be administered orally or intravenously, is currently undergoing phase-2 trials.

With regard to the phenomenon of clopidogrel hyporesponsiveness (or “resistance”), the benefit of changing treatment based on platelet function tests and/or single nucleotide polymorphism (SNP) determination remains unproven. Is clopidogrel hyporesponsiveness a risk marker or a modifiable risk factor? Will the need for platelet function testing and/or SNP determination be obviated by antiplatelet agents under development (eg, prasugrel, ticagrelor) because of their greater and more consistent inhibition of platelet function, or will they result in a greater need for platelet function testing because of their increased risk for hemorrhage?

Small published studies suggest that modifying clopidogrel dose based on the VASP assay or light transmission aggregometry may be of clinical benefit. However, large randomized guided therapy studies are needed to resolve these questions and a number are in progress: GRAVITAS, 3T/2R, DANTE, TRIGGER-PCI, and ARTIC.

In summary, the P2Y₁₂ antagonist clopidogrel has a well-established role as an antithrombotic agent in the settings of PCI and acute coronary syndrome. However, a poor response to clopidogrel as measured by in vitro platelet function assays is associated with a poor clinical response to clopidogrel. Novel P2Y₁₂ antagonists have advantages over clopidogrel, including more rapid, less variable, and more complete inhibition of platelet function. Ongoing studies will determine whether these new P2Y₁₂ antagonists will result in better and/or more rapid antithrombotic effects than clopidogrel, without an unacceptable increase in hemorrhagic or other side effects.

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