latelet-Inhibitor Agents



latelet-Inhibitor Agents


Dominick J. Angiolillo MD, PhD, FACC, FESC, FSCAI

José Luis Ferreiro MD



The rupture or erosion of an atheromatous plaque and subsequent thrombus formation can lead to an acute coronary syndrome (ACS). The rupture of an atherosclerotic plaque may also be iatrogenic, as occurs in the setting of percutaneous coronary interventions (PCI). The exposure of subendothelial collagen after a plaque rupture or erosion allows platelet adhesion, activation, and aggregation at the site of vessel injury. In addition, exposure of tissue factor triggers the extrinsic pathway of the coagulation cascade (1, 2). This is a dynamic process that results in thrombus formation (Fig. 3-1). Advances in the understanding of the complex mechanisms have been pivotal for the development of safer and more efficacious antithrombotic and antiplatelet therapies. (1) This chapter is aimed to review currently available antiplatelet therapies in the setting of PCI.






FIGURE 3-1 Platelet mediated thrombosis. The interaction between glycoprotein Ib (GP Ib) and von Willebrand factor (vWF) mediates platelet tethering, enabling subsequent interaction between GP VI and collagen. This triggers the shift of integrins to a high-affinity state and the release of adenosine diphosphate (ADP) and thromboxane A2 (TXA2) which bind to the P2Y12 and TP receptors, respectively. Tissue factor (TF) locally triggers thrombin formation, which contributes to platelet activation via binding to the platelet protease activated receptor (PAR-1). (Adapted from: Angiolillo DJ et al. Circ J. 2010;74:597-607, with permission.)


ANTIPLATELET THERAPY

Currently, there are three families of antiplatelet agents for the treatment and prevention of recurrent events in patients undergoing PCI (1). These include cyclooxygenase (COX-1) inhibitors, adenosine diphosphate (ADP) P2Y12 receptor antagonists, and glycoprotein (GP) IIb/IIIa inhibitors. Other agents with antiplatelet properties are available, such as cilostazol, dipyridamole, pentoxifylline. However, these agents do not have a clinical indication for prevention of recurrent ischemic events in coronary artery disease (CAD) patients.



ASPIRIN


Mechanisms of Action

Aspirin is an irreversible inhibitor of COX activity of prostaglandin H (PGH) synthase 1 and synthase 2, also known as COX-1 and COX-2, respectively (3). These isoenzymes catalyze the conversion of arachidonic acid to PGH2. The latter serves as a substrate for the generation of several prostanoids, including thromboxane A2 (TXA2) and prostacyclin (PGI2). TXA2, an amplifier of platelet activation and a vasoconstrictor, is mainly derived from platelet COX-1 and is highly sensitive to inhibition by aspirin. Vascular PGI2, a platelet inhibitor and a vasodilator, is derived largely from COX-2 and is less susceptible to inhibition by low doses of aspirin (Fig. 3-2). Only high doses of aspirin can inhibit COX-2, which has anti-inflammatory and analgesic effects, while low doses of aspirin are sufficient to inhibit COX-1 activity, leading to antiplatelet effects (3). Aspirin is rapidly absorbed in the upper gastrointestinal tract and leads to platelet inhibition within 60 minutes. The plasma half-life of aspirin is ˜20 minutes; peak plasma levels of aspirin are achieved within 30 to 40 minutes. Enteric-coated aspirin
delays absorption and increases plasma levels, which require ˜3 to 4 hours. Since aspirin induces an irreversible COX-1 blockade, COX-mediated TXA2 synthesis is prevented for the entire life span of the platelet (˜7-10 days) (3).






FIGURE 3-2 Mechanism of Action of Aspirin. Arachidonic acid, a 20-carbon fatty acid containing four double bonds, is released from membrane phospholipids by several forms of phospholipase A2, which are activated by diverse stimuli. Arachidonic acid is converted by cytosolic prostaglandin H synthases, which have both cyclooxygenase and hydroperoxidase (HOX) activity, to the unstable intermediates prostaglandin G2 and prostaglandin H2, respectively. The synthases are also termed cyclooxygenases and exist in two forms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Low-dose aspirin selectively inhibits COX-1, whereas high-dose aspirin inhibits both COX-1 and COX-2. Prostaglandin H2 is converted by tissue-specific isomerases to multiple prostanoids. These bioactive lipids activate specific cell-membrane receptors of the superfamily of G-protein-coupled receptors, such as the thromboxane receptor, the prostaglandin D2 receptors, the prostaglandin E2 receptors, the prostaglandin F2a receptors, and the prostacyclin receptor. (Adapted from: Patrono C. et al. N Engl J Med. 2005;353:2373-2383, with permission.)



Indications

Aspirin is the mainstay of antiplatelet therapy for secondary prevention of recurrent ischemic events (3). In high-risk patients, particularly those with ACS and undergoing PCI, aspirin should be given as promptly as possible (4, 5). Patients already taking daily aspirin therapy should take 81 to 325 mg prior to PCI, while patients not on aspirin therapy should be given 325 mg nonenteric aspirin prior to PCI (Class I recommendation, level of evidence: B) (5). Aspirin should be continued indefinitely after PCI (Class I recommendation, level of evidence: B). However, the optimal maintenance dose of aspirin for prevention of cardiovascular events has been a subject of controversy. Registry data have shown oral aspirin doses of 75 to 150 mg/day to be as effective as higher doses for long-term prevention of ischemic events (3, 6). Importantly, higher doses of aspirin (>150 mg) do not offer greater protection from recurrent ischemic events, whereas bleeding events, in particular gastrointestinal bleeding, are significantly increased (3, 6). Such registry data are in line with recent randomized clinical trial findings (7). Based on these observations, the updated PCI guidelines state that it is reasonable to consider 81 mg/day in preference to higher maintenance doses as a maintenance regimen (Class IIa recommendation, level of evidence: B) (5).


Side Effects

The side effects of aspirin are primarily gastrointestinal and are dose related. Using low doses (75 to 162 mg/day) reduces these side effects (3). Aspirin use can lead to gastric erosions, hemorrhage, and ulcers that can contribute to anemia. Other interactions and side effects related to aspirin include those due to concomitant treatment with some nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen and ibuprofen (3). These drugs in fact compete for the COX-1 active site and thus interfere with the action of aspirin when administered concomitantly, resulting in attenuation of its antiplatelet effects (3). This may contribute to a reduction in the cardioprotective effects of aspirin. Finally, three types of aspirin sensitivity have been described: respiratory sensitivity (asthma and/or rhinitis), cutaneous sensitivity (urticaria and/or angioedema), and systemic sensitivity (anaphylactoid reaction) (8). Desensitization using escalating doses of oral aspirin can be considered in these patients (8).


P2Y12 INHIBITORS

ADP is one of the main platelet-activating factors and is mediated by the P2Y1 and P2Y12 receptors (1, 9). The P2Y1 and P2Y12 are G-coupled receptors and are required for platelet aggregation. However, ADP-stimulated effects are mediated mainly by P2Y12 receptor activation, which leads to sustained platelet aggregation and stabilization of the platelet aggregate. Inhibition of the P2Y12 signaling pathway is critical, particularly in the setting of PCI, as emerged from seminal studies with ticlopidine, a first-generation thienopyridine. In fact, the combination of aspirin and ticlopidine showed to be associated with better outcomes, in particular the prevention of thrombotic complications, than aspirin monotherapy or aspirin plus warfarin in patients undergoing coronary stenting (10). However, ticlopidine has two major disadvantages: (a) it has a limited safety profile with the nondepreciable rates of agranulocytosis, rash, and gastrointestinal effects; (b) it achieves antiplatelet effects slowly, given that the drug cannot be given under a loading dose because of risk of toxicity.

Clopidogrel, a second-generation thienopyridine, has shown to have a more favorable safety profile than that of ticlopidine, reason for which this has become the thienopyridine of choice in the setting of PCI (11). Clopidogrel has been evaluated in a large number of clinical investigations in the course of the past decade, supporting its role in the setting of ACS and PCI (12) (Table 3-1). However, clopidogrel also presents limitations, the most important of which is its broad range in interindividual antiplatelet drug effects (13). In particular, a considerable number of patients persist with high platelet reactivity despite clopidogrel therapy, exposing them to an increased risk of recurrent ischemic events, including stent thrombosis (13). This has set the basis for the development of newer generation P2Y12 receptor inhibitors. These include prasugrel, a third-generation thienopyridine, and ticagrelor, a first-in-class cyclopentyltriazolopyrimidine (CPTP), which are already approved for clinical use (Table 3-2) (12). In addition, the emerging amount of prognostic data deriving from platelet function and genetic testing has also led guidelines to implement recommendations for the use of these tests (Table 3-3) (4, 5). Overall, despite the large number of studies associating results of platelet function and genetic testing with adverse outcomes, particularly in the setting of PCI, the lack of data from large-scale clinical trials showing how results of these tests can lead to changes in therapy resulting in improved outcomes argues against their routine use.


Mechanisms of Action

Thienopyridines (ticlopidine, clopidogrel, and prasugrel) are oral prodrugs, and thus need to be metabolized by the hepatic cytochrome P450 (CYP) system to give rise to an active metabolite that irreversibly inhibits the P2Y12 receptor (Fig. 3-3) (12, 13). Clopidogrel is a second-generation thienopyridine, which requires a two-step oxidation by the CYP system to generate an active metabolite (12, 13). However, ˜85% of the prodrug is hydrolyzed by prehepatic esterases to an inactive carboxylic acid derivative, and only ˜15% of the prodrug is metabolized by the CYP system into an active metabolite. Multiple CYP enzymes are involved in this process; among these, CYP2C19 is pivotal as this is involved in both metabolic steps of clopidogrel. This explains why genetic variants associated with reduced metabolic activity of the CYP2C19 enzyme or drugs interfering with its activity, such as certain proton pump inhibitors (PPIs), can reduce the antiplatelet effects of clopidogrel. Prasugrel is a third-generation thienopyridine, which has a more efficient metabolism than does clopidogrel (14, 15). After oral ingestion, the prodrug is exposed to hydrolysis by carboxyesterases, mainly in the intestine, giving rise to an intermediate thiolactone, which then requires only a single-step hepatic metabolism (Fig. 3-3). In turn, the active metabolites are generated more rapidly and effectively (14, 15). This more favorable pharmacokinetic profile translates into better pharmacodynamic effects, showing more potent platelet inhibition, lower interindividual variability, and a faster onset of antiplatelet activity than with clopidogrel, even when the latter is used at a high dose (>600 mg) (14, 15). A 60-mg loading dose of prasugrel achieves 50% platelet inhibition by 30 minutes and 80% to 90% inhibition by 1 to 2 hours (14, 15). Although clopidogrel and prasugrel have a half-life of only ˜8 hours, they have
an irreversible effect on platelets, which lasts till their life span (7 to 10 days) (12).








TABLE 3-1 Large-Scale Randomized Clinical Trials Evaluating the Efficacy of Dual Antiplatelet Therapy with Aspirin and an Orally Administered P2Y12 Receptor Inhibitor in ACS/PCI Patients



























































































Study

N

Study Drugs

Setting

Primary Endpoint

Resultsa


CURE

12,562

Aspirin + clopidogrelbvs. aspirin

UA/NSTEMI

Cardiovascular death, nonfatal MI, or stroke at 1 year

9.3% vs. 11.4%; RR = 0.80 (0.72-0.90)


PCI-CURE

2,658

Aspirin + clopidogrelbvs. aspirin

PCI patients from CURE

Cardiovascular death, MI, or urgent TVR at 30 days

4.5% vs. 6.4%; RR = 0.70 (0.50-0.97)


CREDO

2,116

Aspirin + clopidogrelbvs. aspirin

Elective PCI

Death, MI, or stroke at 1 year

8.5% vs. 11.5%; RRR = 26.9% (3.9%-44.4%)


COMMIT

45,852

Aspirin + clopidogrelbvs. aspirin

Acute MI (93% STEMI)

Death, reinfarction, or stroke at discharge or at 28 days

9.2% vs. 10.1%; OR = 0.91 (0.86-0.97)


CLARITY

3,491

Aspirin + clopidogrelbvs. aspirin

STEMI with fibrinolysis

Occluded infarct-related artery on angiography, death, or recurrent MI before angiography

15.0% vs. 21.7%; OR = 0.64 (0.53-0.76)


PCI-CLARITY

1,863

Aspirin + clopidogrelbvs. aspirin

PCI patients from CLARITY

Cardiovascular death, recurrent MI, or stroke at 30 days

3.6% vs. 6.2%; OR = 0.54 (0.35-0.85)


CURRENT-OASIS 7

25,086

Aspirin + double-dose clopidogrelbvs. aspirin + standard-dose clopidogrelb

ACS patients referred for invasive strategy

Cardiovascular death, MI, or stroke at 30 days

4.2% vs. 4.4%; HR = 0.94 (0.83-1.06)


CURRENT-OASIS 7 (PCI cohort)

17,263

Aspirin + double-dose clopidogrelbvs. aspirin + standard-dose clopidogrel

PCI patients from CURRENT-OASIS 7

Cardiovascular death, MI, or stroke at 30 days

3.9% vs. 4.5%; HR = 0.86 (0.74-0.99)


TRITON-TIMI 38

13,608

Aspirin + prasugrel vs. aspirin + clopidogrelb

ACS patients undergoing PCI

Cardiovascular death, nonfatal MI, or nonfatal stroke up to 15 months

9.9% vs. 12.1%; HR = 0.81 (0.73-0.90)


PLATO

18,624

Aspirin + ticagrelor vs. aspirin + clopidogrelb

ACS patients

Death from vascular causes, MI, or stroke at 12 months

9.8% vs. 11.7%; HR = 0.84 (0.77-0.92)


PLATO (invasive)

13,108

Aspirin + ticagrelor vs. aspirin + clopidogrelb

PCI patients from PLATO

Death from vascular causes, MI, or stroke at 12 months

8.9% vs. 10.6%; HR = 0.84 (0.75-0.94)


ACS, acute coronary syndrome; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention; RR, relative risk; RRR, relative risk reduction; STEMI, ST-elevation myocardial infarction; TVR, target vessel revascularization; UA, unstable angina; CURE, Clopidogrel in Unstable Angina to Prevent Recurrent Events trial; CREDO, Clopidogrel for the Reduction of Events During Observation trial; COMMIT, Clopidogrel and Metoprolol in Myocardial Infarction trial; CLARITY, Clopidogrel as Adjunctive Reperfusion Therapy trial; CURRENT-OASIS-7, Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Intervention trial; TRITON, Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel; PLATO, Platelet Inhibition and Outcomes.


a Results are expressed as percentage of events and association measure (95% confidence interval).

b Clopidogrel was given as a loading dose of 300 mg and then 75 mg daily in CURE, CREDO, CLARITY, and COMMIT. In CURRENT/OASIS 7, double-dose clopidogrel was defined as a 600-mg loading dose and 150 mg once daily for 7 days, followed by 75 mg once daily; standard-dose clopidogrel was defined as a 300-mg loading dose, followed by 75 mg once daily. Patients were also randomized to receive low-dose (75-100 mg/day) or high-dose (300-325 mg/day) aspirin. Prasugrel was given as a 60-mg loading dose, followed by 10 mg once daily. Ticagrelor was given as a 180-mg loading dose, followed by 90 mg twice daily.


Ticagrelor is the first nonthienopyridine forming part of a new class of P2Y12 inhibitors called CPTP approved for clinical use (16

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May 28, 2016 | Posted by in CARDIOLOGY | Comments Off on latelet-Inhibitor Agents

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